Immunology Exam 2:

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C3d:

*A protein that covalently binds to microbes and serves as a ligand for a co-receptor that enhances B cell responses to antigens* C3d is a complment protein fragment that binds covalently to microbial surfaces. C3d serves as the link between the BCR, which binds directly to the microbe, and the CR2 co-receptor. This cross-linking between the BCR and CR2 serves to amplify the B cell response 1000-fold, when compared with immune responses in which CR2 is not recruited. CR2 forms a complex with two other proteins, CD19 and CD81, on the B cell surface. When CD19 is brought into proximity with BCR-associated kinases, the cytoplasmic tail of CD19 is rapidly phosphorylated. CD19 then activates several signaling pathways, including P13-kinase.

The maturation of B and T lymphocytes involves a series of events that occur in the generative lymphoid:

1. The commitment of progenitor cells to the B lymphoid or T lymphoid lineage 2. Proliferation of progenitors and immature committed cells at specific early stages of development, providing a large pool of cells that can generate useful lymphocytes 3. The sequential and ordered rearrangement of antigen receptor genes and the expression of antigen receptor proteins (rearrangement and recombination are used interchangeably) 4. Selection events that preserve cells that have produced functional antigen receptor proteins and eliminate potentially dangerous cells that strongly recognize self antigens. These checkpoints during development ensure that lymphocytes that express functional receptors with useful specificities will mature and enter the peripheral immune system 5. Differentiation of B and T cells into functionally and phenotypically distinct subpopulations. *B cells develop into follicular, marginal zone, and B-1 cells.* *T cells develop into CD4+ and CD8+ αβ T lymphocytes, NKT cells, and γδ T cells.*

Adhesion molecules cloned so far belong to four main protein families:

Integrins Selectins CAMs (cell adhesion molecules) Proteoglycan-link core proteins

Structure of secretory IgA (sIgA):

J chain is for trafficking Secretory component is crucial to make sure the antibody is not degraded

When recombination/rearrangement is occurring in a gene, what is the first step?

Joining D to J

The second step of recombination/rearrangement is:

Joining V to DJ

IgA antibody:

Know J chain and secretory component

Diffuse MALT (D-MALT):

Lamina propria lymphocytes (primarily B cells); LP is major site of Ig synthesis Derived from O-MALT and represent effector and memory cells from cells stimulated by antigens Intra-epithelial lymphocytes (IELs) Plasma cells producing dimeric IgA Antigen-presenting cells (macrophages and dendritic cells)

IgA class switching:

Large amounts of IgA production in the gut is partially due to selective induction of IgA isotype switching Occurs in B cells in the GALT and mesenteric lymph nodes T-dependent or T-independent pathways *Many soluble proteins and cytokines induce isotype switching (ex. TGF-B)*

Lymphocyte development:

Lymphocytes express highly diverse antigen receptors that are capable of recognizing a wide variety of foreign substances This diversity is generated during the development of mature B and T lymphocytes from precursor cells that do not express antigen receptors and cannot recognize and respond to antigens The process by which lymphocyte progenitors in the thymus and bone marrow differentiate into mature lymphocytes that populate peripheral lymphoid tissue is called *lymphocyte development* or *lymphocyte maturation*

Conclusions:

LysM proteins are found in mammals LysM proteins participate in regulation of innate immunity LysM proteins sense chitin

Plant LysM motif-containing receptors:

Lysin motif (LysM) receptor kinases recognize microbe-derived N-acetylglucosamine-containing ligands CERK1/CERK5 is critically important for chitin signaling in Arabidopsis KO mutants completely lose ability to respond to chitin elicitors

M cells:

M-cells may serve as entry sites for many pathogenic microorganisms

Organization of mucosal lymphoid tissue:

MALT (mucosa associated lymphoid tissue) cellular mass exceeds total lymphoid cells in bone marrow, thymus, spleen, and lymph nodes GALT = Gut associated lymphoid tissue BALT = Bronchi associated lymphoid tissue NALT = Nasal associated lymphoid tissue

J chain:

MW = 15,600 kD Associated with polymeric Ig (IgM and IgG) Synthesized by plasma cells One J chain per polymer, regardless of size Is probably associated with initiation of polymerization

Secretory component:

MW = 80,000 kD Synthesized by epithelial cells of mucous membranes IgA dimer binding sites per epithelial cell = approximately 260-7,000

Roles of TH1 cells - mutual activation of macrophages and T cells:

Macrophages are activated by CD40L-CD40 interactions and by IFN-γ expressed by TH1 cells and perform several functions that kill microbes, stimulate inflammation, and enhance the antigen-presenting capacity of the cells. Responses of activated macrophages = enhanced killing of phagocytosed bacteria, secretion of inflammatory cytokines, increased expression of molecules required for T cell activation

Fungal recognition:

Many members of the fungal kingdom are responsible for disease - Aspergillus fumigatus (invasive) - Candida albicans (invasive) - Alternaria alternata (atopy) - Cryptococcus neoformans Innate immune cell recognize a variety of fungal PAMPs

Organization of a lymph node:

Mature T and B cells migrate to peripheral tissues to encounter foreign antigens

"Clonal ignorance":

Mature self-reactie lymphocyte clones do not encounter or respond to self antigens

Peripheral tolerance:

Mature self-reactive lymphocytes that recognize self antigens in peripheral tissues are inactivated (anergy), killed (deletion), or suppressed by regulatory T cells

Regulatory T cells continued..

Mechanism of action: may be multiple - secretion of immune-suppressive cytokines - CTLA-4 on T-regs blocks B7 on APCS Significance for self-tolerance: - Some autoimmune diseases may be associated with defects in regulatory T cells or resistance of responding cells to suppression - therapeutic potential of cellular therapy (autoimmune diseases, graft rejection, etc)

Class switching:

Mechanisms of heavy chain isotype switching: When antigen-activated B cells encounter helper T cell signals (CD40L and cytokines), the B cells undergo switching to Ig isotypes other than IgM (in this example, IgE).

Memory T cells:

Memory T cells that are generated by T cell activation are long-lived cells with an enhanced ability to react against the antigen These cells are present in the recirculating lymphocyte pool and are abundant in mucosal tissues and the skin as well as in lymphoid organs After a T cell response wanes, there are many more memory cells of the responding clone than there were naive T cells before the response These memory cells respond rapidly to subsequent encounter with the antigen and generate new effector cells that eliminate the antigen

Antigen sampling by intestinal dendritic cells:

Microbial antigens in the gut lumen can be sampled by lamina propria dendritic cells that extend cytoplasmic processes between the intestinal epithelial cells Antigen-sampling dendritic cells are numerous in certain regions of the intestine, especially the terminal ileum where they extend dendrites through the junctions between adjacent epithelial cells, apparently without disrupting the tight junctions --- Dendritic cells are present in the intestinal mucosa and sample antigens for presentation to T cells in GALT and mesenteric lymph nodes. Some dendritic cells extend dendritic processes between intestinal epithelial cells in the lumen to sample antigens. Macrophages may also sample luminal antigens in this manner. Other dendritic cells present in the lamina propria sample antigens that are derived from lumina contents and and have gotten through the epithelial barrier.

Antigen sampling by intestinal dendritic cells:

Alta1:

More than 98% of Alternaria allergic patients show specific IgE to Alta1, a specific secreted protein of unknown function A unique B-barrel structure that potentially binds flavonoid like compounds

Zika virus is spread by:

Mosquitos

Summary pt. 3:

Most autoimmune diseases are polygenic, and numerous susceptibility genes contribute to disease development. *The greatest contribution is from MHC genes*; other genes are believed to influence the selection or regulation of self-reactive lymphocytes *Infections may predispose to autoimmunity by several mechanisms, including enhanced expression of co-stimulators in tissues and cross-reactions between microbial antigens and self antigens.* Some infections may protect individuals from autoimmunity, by unknown mechanisms.

Introduction to mucosal immunity:

Mucosa represent a vast surface area - vulnerable to colonization and invasion The total amount of IgA exceeds circulating IgG IgA = on mucosal surfaces, respiratory and GI tract, highest concentration in the body IgG = circulating in blood Antigens are separated from mucosal immune tissue by epithelial barriers Antigens must be transported across the epithelium

Antigen sampling across simple epithelia:

Mucosal surfaces generally lined by a single layer of epithelial cells Barrier sealed by tight junctions that exclude peptides and macromolecules Uptake of antigen requires active trans-epithelial transport (M cells or dendritic cells) Sampling is blocked by mechanisms such as local secretions, sIgA, mucins, etc.

Role of CD40 in T cell activation:

Naive T cells are activated by peptide-MHC complexes on activated APCs. Antigen recognition by T cells together with some co-stimulation induces the expression of CD40 ligand (CD40L) on the activated T cells. CD40L engages CD40 on APCs and may stimulate the expression of more B7 molecules and the secretion of cytokines that activate T cells. Thus, CD40L on the T cells makes the APCs better at promoting and amplifying T cell activation.

Activation of naive and effector T cells by antigens:

Naive T cells circulate through lymph nodes and find antigens --> activation of naive T cells in lymph node, causes development of effector cells --> activation of effector T cells at the site of infection; eradication of the microbe Antigens that are transported by dendritic cells to lymph nodes are recognized by naive T lymphocytes that recirculate through these lymph nodes. The T cells are activated to differentiate into effector cells, which may remain in the lymphoid organs to help B lymphocytes or migrate to sites of infection, where the effector cells are again activated by antigens and perform their various functions (such as macrophage activation)

Modulation of homing specificities:

Naive lymphocytes prior to antigenic stimulation demonstrate no migration preference Following antigen stimulation, lymphocytes acquire homing specificities

Negative selection:

Negative selection eliminates developing thymocytes whose TCR binds TOO STRONGLY to self antigen-MHC complexes Negative selection leads to apoptosis actively induced by antigen-receptor recognition of self antigens

Key players in late phase reaction:

Network of inflammatory cells: eosinophils (50% of infiltrate), allergen-specific T cells, mast cells, basophils, TH1 cells Sometimes TH17 cells and neutrophils (severe form of asthma)

Immunologic tolerance:

Normal response = effector and memory T cells *** Anergy = functional unresponsiveness Deletion = apoptosis (activation-induced cell death) Suppression = regulatory T cell blocks activation

LysM proteins are widespread in nature and associated with host-pathogen interactions:

Numerous fungal plant pathogens secrete LysM proteins -- function as "effectors" masking chitin (stealth) Bacteria have LysM proteins, mostly as cell wall components LysM proteins in shrimp and crayfish are important for bacterial and viral clearance (shown to bind LPS, chitin, viral glycoproteins, etc.) No studies on mammalian receptor-like LysM proteins (one in brain but is a large enzyme involved in oxidative stress)

Organized lymphoid follicles at specific mucosal sites (O-MALT):

Occur in tissues of digestive, respiratory, and genital mucosal surfaces Ex. Waldeyer's tonsillar ring Light germinal centers Dark adjacent areas populated by B and T lymphocytes and antigen-presenting cells Site of antigen sampling and generation of effector and memory cells

Mechanisms of helper T cell-mediated B cell activation:

On activation, helper T cells express CD40 ligand (CD40L), which engages CD40 on antigen-stimulated B cells and induces B cell proliferation and differentiation, initially in extra-follicular foci and later in germinal centers

Mechanisms of helper T cell-mediated B cell activation:

On activation, helper T cells express CD40 ligand (CD40L), which engages its receptor, CD40, on antigen-stimulated B cells and induces B cell proliferation and differentiation, initially in extra-follicular foci and later in germinal centers

Relationship between systemic and mucosal immunity:

Oral tolerance (anergy) - oral administration of antigen suppresses systemic immunity "Mucosal internet" - epithelial cell-immune cell interactions - may be critical for induction of adaptive response - danger theory

PAMPs:

Pathogen associated molecular pattern

Phases of the humoral immune response:

Continued..

Primary immune response-naive B cells are stimulated by antigens, become activated, and differentiate into antibody-secreting cells that produce antibodies specific for the eliciting antigen Secondary immune response = elicited when the same antigen stimulates memory B cells, leading to production of greater quantities of specific antibody than are produced in the primary response In a primary immune response, naive B cells are stimulated by antigen, become activated, and differentiate into antibody-secreting cells that produce antibodies specific for the eliciting antigen. A secondary immune response is elicited when the same antigen stimulates memory B cells, leading to production of greater quantities of specific antibody than are produced in the primary response.

T cell expansion and differentiation:

Primary signals for T cell expansion = TCR ligation (MHC+antigen), co-stimulatory molecules Primary signals for T cell differentiation = cytokines

*Interferon-γ:*

Produced by T cells and NK cells --> activates macrophages: classical activation (increased microbicidal functions) B cells: isotype switching to opsonizing and complement-fixing IgG subclasses (established in mice) T cells: TH1 differentiation Various cells: increased expression of class I and class II MHC molecules, increased antigen processing and presentation to T cells *Suppression of TH2 by TH1 cells may be mediated by Interferon-gamma*

Secretory IgA:

Produced in the GALT (gut associated lymphoid tissue) and mesenteric lymph nodes ~2 g of sIgA per day Isotypes (A1 and A2) are tissue specific... A2 = mucosal plasma cells (resistant to IgA1 proteases)

Antigen-mediated cross-linking of the BCR complex:

Production of proteins that promote survival and proliferation, expression co-stimulators and cytokine receptors that promote interactions with and responsiveness to helper T cells Migration of the cells toward T cells as a result of the expression of CCR7.. Antigen-induced cross-linking of the B cell antigen receptor induces several cellular responses including: production of proteins that promote survival and proliferation, expression of co-stimulators and cytokine receptors that promote interactions with and responsiveness to helper T cells, and migration of the cells toward T cells as a result of the expression of CCR7.

Macrophage activation:

Production of reactive oxygen species, nitric oxide, increased lysosomal enzymes --> killing of microbes in phagolysosomes (effector function of macrophages) Secretion of cytokines (TNF, IL-1, IL-12) and chemokines --> TNF, IL-1, chemokines = leukocyte recruitment and inflammation; IL-12 = TH1 differentiation and IFN-gamma production Increased expression of B7 co-stimulators, MHC molecules --> increased T cell activation (amplification of T cell response)

Macrophage responses/role in cell-mediated immunity:

Production of reactive oxygen species, nitric oxide, increased lysosomal enzymes --> killing of microbes in phagolysosomes (effector function of macrophages) Secretion of cytokines (TNF, IL-1, IL-12) and chemokines --> TNF, IL-1, chemokines: leukocyte recruitment (inflammation). IL-12: TH1 differentiation, IFN-gamma production Increased expression of B7 co-stimulators, MHC molecules --> increased T cell activation (amplification of T cell response)

Antigen presentation on B cells to helper T cells:

Protein antigens that are recognized by specific B cell antigen receptors are endocytosed and processed to generate peptides that bind to class II MHC molecules and are presented to CD4+ T cells Antigen presentation on B cells to helper T cells: Protein antigens recognized by membrane Ig are endocytosed and processed, and peptide fragments are presented in association with class II MHC molecules. Helper T cells recognize MHC-peptide complexes on the B cells and then stimulate B cell responses. In responses to hapten-carrier conjugates, the hapten (the B cell epitope) is recognized by a specific B cell, the conjugate is endocytosed, the carrier protein is processed in the B cell, and peptides from the carrier (the T cell epitopes) are presented to the helper T cell.

Antigen presentation on B cells to helper T cells:

Protein antigens that are recognized by specific B cell antigen receptors are endocytosed and processed to generate peptides that bind to class II MHC molecules and are presented to CD4+ T cells Summary: Protein antigens recognized by membrane Ig are endocytosed and processed, and peptide fragments are presented in association with class II MHC molecules. Helper T cells recognize MHC-peptide complexes on the B cells and then stimulate B cell responses. In responses to hapten-carrier conjugates, the hapten (the B cell epitope) is recognized by a specific B cell, the conjugate is endocytosed, the carrier protein is processed in the B cell, and peptides from the carrier (the T cell epitopes) are presented to the helper T cell.

Identify the J chain

Purple

Central T cell tolerance:

Recognition of self antigens by immature T cells in the thymus leads to the death of the cells (negative selection, or deletion) or to the development of regulatory T cells that enter peripheral tissues.

Why do Ig and TCR genes only undergo rearrangements in B and T cells, but not in other cell types?

Recombinase activating genes (RAG-1 and RAG-2) are expressed only in developing lymphocytes

TH17 cells combat microbes by ______.

Recruiting leukocytes, mainly neutrophils, to sites of infection

Humoral immune response to T cell-dependent protein antigens:

Sequence of events in humoral immune responses to T cell-dependent protein antigens. (1) Immune responses are initiated by the recognition of antigens by B cells and CD4+ T cells. (2) The activated lymphocytes migrate toward one another and interact, resulting in B cell proliferation and differentiation. (3) Restimulation of B cells by helper T cells in extrafollicular sites leads to early isotype switching and short-lived plasma cell generation, while activation of T cells by B cells results in the induction of follicular helper T cells. (4) The late events occur in germinal centers and include somatic mutation and the selection of high-affinity cells (affinity maturation), additional isotype switching, memory B cell generation, and the generation of long-lived plasma cells.

Gene rearrangement:

Although a B cell can display as many as 100,000 BCR on its surface, every mature B cell produces one and only one kind of BCR or antibody (made up of only one kind of Hc and Lc). The mix and match strategy is used to make the final Hc and Lc genes of each B cell so the receptors on different B cells are so diverse that collectively, our B cells can likely recognize any organic molecule that could exist Select D and J segments, joined together by deleting the DNA sequences in between them. Then V segment chosen. Rearranged gene segments are tested. Protein translation. If gene segments are not in frame (stop codon) --> piece of protein. 1 in 9 chance. Productive rearrangement. Signal to losing chromosome to stop.

Cells that express CD4 are ____.

B and C. Helper T cells and T-reg cells

Conclusions (pt 1):

B and T lymphocytes arise from a common bone marrow-derived precursor that becomes committed to the lymphocyte lineage B cell maturation proceeds in the bone marrow, whereas early T cell progenitors migrate to and complete their maturation in the thymus Early maturation is characterized by cell proliferation induced by cytokines, mainly IL-7, leading to an expansion in the numbers of lymphocytes that have just committed to individual lineages

Structure of C1:

C1q consists of six identical subunits arranged to form a central core and symmetrically projecting radial arms. The globular heads at the end of each arm, designated H, are the contact regions for immunoglobulin. C1r and C1s form a tetramer composed of two C1r and two C1s molecules. The ends of C1r and C1s contain the catalytic domains of these proteins. One C1r2s2 tetramer wraps around the radial arms of the C1q complex in a manner that juxtaposes the catalytic domains of C1r and C1s. *Only antibodies bound to antigens, and not free circulating antibodies, can initiate classical pathway activation*

Match each receptor with the ligand that binds the receptor:

CD28 = B7-1, B7-2 CD2 = LFA-3 CD4 = Class II MHC

Mechanisms of T cell co-stimulation by CD28:

CD28:B7 Causes cell survival, proliferation, and differentiation into effector and memory cells

Role of T cells in eradicating infections:

CD4+ T cells recognize antigens of phagocytosed and extracellular microbes and produce cytokines that activate the phagocytes to kill the microbes and stimulate inflammation. CD8+ T cells can also secrete cytokines and participate in similar reactions. CD8+ cytotoxic T lymphocytes (CTLs) recognize antigens of microbes residing in the cytosol of infected cells and kill the cells.

The role of T cells in eradicating infections:

CD4+ T cells recognize antigens of phagocytosed and extracellular microbes and produce cytokines that activate the phagocytes to kill the microbes/stimulate inflammation. CD8+ T cells can also secrete cytokines and participate in similar reactions. CD8+ cytotoxic T lymphocytes (CTLs) recognize antigens of microbes residing in the cytosol of infected cells and killed the cells.

T helper cells --> differentiation of CD8+ T lymphocytes

CD4+ helper T cells produce cytokines that stimulate CTL differentiation CD4+ helper T cells enhance the ability of APCs to stimulate CTL differentiation

T-cell review:

CD8 = T cell receptor on the cytotoxic T cell, recognizes MHC class 1 + peptide on the target cell CD4 = binds to MHC class II on antigen-presenting cells

Distinct types of effector T cells:

CD8 cytotoxic T cells = kill virus infected cells, pathogens targeted are viruses and some intracellular bacteria CD4 TH1 cells = activate infected macrophages and provide help to B cells for antibody production. Pathogens targeted are microbes that persist in macrophage vesicles and extracellular bacteria CD4 TH2 cells = provide help to B cells for antibody production, especially switching to IgE. Pathogens targeted = helminth parasites. CD4 TH17 cells = enhance neutrophil response. Pathogens targeted = extracellular bacteria CD4 regulatory T cells = suppress T-cell responses *CD4+ can be T helper or T reg cells*

Summary continued..

CD8+ CTLs kill cells that express peptides derived from cytosolic antigens (ex, viral antigens) that are presented in association with class I MHC molecules. CTL-mediated killing is mediated mainly by granule exocytosis, which releases granzymes and perforin. Perforin facilitates granzyme entry into the cytoplasm of target cells. Granzymes initiate several pathways of apoptosis. CD8+ T cels also secrete IFN-gamma and thus may participate in defense against phagocytosed microbes and in DTH reactions.

Mechanisms of CTL killing of target cells:

CTLs kill target cells by two main mechanisms: 1. Complexes of perforin and granzymes are released from the CTL by granule exocytosis and enter target cells. The granzymes are delivered into the cytoplasm of the target cells by a perforin-dependent mechanism, and they induce apoptosis 2. FasL is expressed on activated CTLs, engages Fas on the surface of target cells, and induces apoptosis The major cytotoxic proteins in the granules of CTLs (and NK cells) are granzymes and perforin

Complement activation/formation of the MAC:

Cell-associated C5 convertase cleaves C5 and generates C5b, which becomes bound to the convertase. C6 and C7 bind sequentially and the C5b, 6, 7 complex inserts in the plasma membrane, followed by insertion of C8 Up to 15 C9 molecules may the polymerize around the complex to form the MAC, which creates pores in the membrane and induces lysis C5a released on proteolysis of C5 stimulates inflammation

Complement activation and formation of MAC:

Cell-associated C5 convertase cleaves C5 and generates C5b, which becomes bound to the convertase. C6 and C7 bind sequentially, and the C5b,6,7 complex inserts into the plasma membrane, followed by insertion of C8. Up to 15 C9 molecules may then polymerize around the complex to form the MAC, which creates pores in the membrane and induces cell lysis. C5a released on proteolysis of C5 stimulates inflammation.

Ig heavy chain isotype switching:

Cells activated by helper T cell signals (CD40L, cytokines) undergo switching to different Ig isotypes, which mediate distinct effector functions The role of IFN-gamma in directing specific isotype switching events has been established only in rodents Principle effector functions: IgM = complement activation IgG1, IgG3 = opsonization and phagocytosis, complement activation, neonatal immunity (placental transfer) IgE, IgG4 = immunity against helminths. Mast cell degranulation (immediate hypersensitivity) IgA = mucosal immunity (transport of IgA through epithelia)

Ig heavy chain isotype switching:

Cells activated by helper T cell signals (CD40L, cytokines) undergo switching to different Ig isotypes, which mediate distinct effector functions.

CTL (CD8+ T cells) mainly kill...

Cells with intracellular infections, ex. viruses and cancer

Tolerance in B lymphocytes:

Central tolerance: - deletion of immature cells by high-affinity antigen recognition in the bone marrow - some immature cells may change their antigen receptors when they encounter antigens in the bone marrow ("receptor editing") Peripheral tolerance: - Anergy - Exclusion from lymphoid follicles, death because of loss of survival signals

Chitin immunogenicity:

Chitin-induced accumulation of IL-4-expressing immune cells Independent of LPS-sensing receptor, TLR4 Accumulation was abolished when chitin was treated with IL-4/IL-13 inducible mammalian chitinase Also abolished when chitin was injected into mice overexpressing this chitinase

Continued...

Chromatin may therefore exist as relatively loosely packed structures, called euchromatin, wherein genes are available and are transcribed, or as very tightly packed structures called heterochromatin, in which genes are maintained in a silenced state. The structural organization of portions of chromosomes therefore varies in different cells, making certain genes available for transcription factors to bind to while these very same genes may be unavailable to transcription factors in other cells.

A helper T cell response to a protein antigen requires the participation of antigen-presenting cells that express which of the following types of molecules?

Class II MHC and co-stimulators

"Allergy" origins:

Clemens von Pirquet (1874-1929) - Austrian scientist and physician first coined the term allergy, propensity of some individuals to develop signs and symptoms of reactivity, hypersensitive reactions, when exposed to certain substances Allergy or Atopy comes from "Atopos" = greek for meaning out of place Associated with the production of allergen-specific IgE and expansion of allergen-specific T cell populations

The combination of TCR and costimulatory signals induces naive T cells to express IL-2 and high affinity IL-2 receptors. This results in which of the following functional responses by the T cell?

Clonal expansion

IL-2:

Clonal expansion - IL-2 is the major autocrine growth factor for T cells. Naive T cells express two chains of the IL-2 receptor which bind IL-2 with low affinity. Antigen and co-stimulatory signals induce IL-2 production and expression of a third chain (CD25) of the receptor, which increases the affinity for IL-2. The T cell thus enters the cell cycle in response to IL-2 signals and undergoes several rounds of proliferation, thereby expanding the clone of T cells specific for the inciting antigen *The combination of TCR and co-stimulatory signals induces naive T cells to express IL-2 and high affinity IL-2 receptors*

T cell exhaustion...

D. *May have evolved as means to attenuate the tissue-damaging consequences of chronic viral infection*

CTLs are the major defense against which of the following class of organisms? A. Extracellular bacteria B. Fungi C. Protozoans D. Viruses E. Helminths

D. *Viruses* CTLs kill host cells with intracellular infections (MHC class 1 present to CD8+ T cells, only intracellular infections). All viruses must reproduce within host cells and are eradicated by CTL killing of the cells they infect. CTLs have little capacity to kill extracellular microbes since they are activated by MHC class 1 complexes, which are found in all nucleated cells and deal with intracellular infections (viruses and cancer). Therefore, CTLs do not kill extracellular bacteria. Most protozoans, fungi, and helminths are also extracellular.

Infectious microbes may contain antigens that cross-react with self antigens, so immune responses to the microbes may result in reactions against self antigens. This phenomenon is called _____.

D. Molecular mimicry

DAMPs:

Damage associated molecular pattern

Autoimmunity:

Definition = immune response against self (auto-) antigen, by implication pathologic General principles: - Pathogenesis: the development of autoimmunity reflects a combination of susceptibility genes and environmental triggers (usually infections) - Different autoimmune diseases may be systemic or organ-specific; may be caused by different types of immune reactions (antibody- or T cell-mediated) Challenges in understanding pathogenesis of autoimmune diseases: - failure to identify target antigens, heterogenous disease manifestations, disease may present long after initiation - recent advances: identifying self antigens (MS, type 1 diabetes); genetic analyses; improved methods for studying immune system of patients

Immunologic tolerance:

Definition: Specific unresponsiveness by lymphocytes to an antigen Immunocompetent host fails to respond to an immunogenic challenge to a specific antigen Significance: Immunocompetent hosts are tolerant to their own antigens; breakdown of self-tolerance leads to auto-immunity Therapeutic potential: Inducing tolerance may be exploited to prevent graft rejection, hypersensitivity to diets, treat autoimmune and allergic diseases, and prevent immune responses in gene therapy, perhaps stem cell transplantation

Sex-based differences in autoimmunity:

Differences can be traced to sex hormones - Estrogen - TH1 dominated immune responses promote inflammation - prolactin secretion (helps regulate immune response), CRH (corticotropin-releasing hormone) that promotes cortisol secretion - Testosterone (cause autoimmunity or protect against it) - Pregnancy: - More of TH2-like response, hormones creates an anti-inflammatory environment (ex. high cortisol) - Diseases enhanced by TH2-like responses are exaggerated and diseases that involve inflammatory responses are suppressed

Induction and effector phases of CD8+ T cell responses:

Differentiation of CD8+ T cells into effector CTLs involves acquisition of the machinery to kill target cells The infected or tumor cell that is killed by CTLs is commonly called the target cell. Naive CD8+ cells recognize antigens but need to proliferate and differentiate to generate a sufficiently large pool of CTLs to destroy the source of the antigen Within the cytoplasm of differentiated CTLs are numerous modified lysosomes (called granules) that contain proteins, including perforin and granzymes, whose function is to kill other cells. In addition, differentiated CTLs are capable of secreting cytokines, mostly IFN-γ, that function to activate phagocytes.

Genetics of autoimmunity: challenges =

Difficult to relate complex genotypes to phenotypic and functional abnormalities, to better understand pathogenesis Limitations of GWAS: misses rare mutations Identified disease-associated polymorphisms have small effects, therefore little predictive value Because of small effects of any one gene, targeting these genes therapeutically is unlikely to have significant benefit

Antigen presenting cells (APCs) perform which of the following functions in adaptive immune responses?

Display MHC-associated peptides on their cell surfaces for surveillance by T lymphocytes

Migration and homing of lymphocytes:

Distribution of Homing Specificities in Mucosal Tissues - Epithelial cells lining postcapillary venules (HEV's) display organ-specific recognition sites called "vascular addressins" - Recognized by cell adhesion molecules "homing receptors"

Checkpoints in lymphocyte maturation:

During development, the lymphocytes that express receptors required for continued proliferation and maturation are selected to survive, and cells that do not express functional receptors due by apoptosis. Positive selection and negative selection further preserve cells with useful specificities. The presence of multiple checkpoints ensure that only cells with useful receptors complete their maturation.

Conclusions (pt 2):

Extracellular signals induce the activation of transcription factors that induce the expression of lineage-specific genes and open up specific antigen receptor gene loci at the level of chromatin accessibility B and T cell development involves the somatic rearrangement of antigen receptor gene segments and the initial expression of the Ig heavy chain μ protein in B cell precursors and TCR β molecules in T cell precursors. The initial expression of pre-antigen receptors and the subsequent expression of antigen receptors are essential for the survival, expansion, and maturation of developing lymphocytes and for selection processes that lead to a diverse repertoire of useful antigen specificities.

FasL =

FasL is expressed on the surface of the CTL, not in granules. FasL binding to Fas on target cells may induce apoptosis of the target cells by a caspase-dependent pathway, but this is a minor mechanism of CTL killing relative to perforin and granzyme B dependent mechanisms.

______ is a technology that is used to analyze the physical and chemical characteristics of particles in a fluid as it passes through at least one laser.

Flow cytometry

Flow cytometry:

Flow cytometry is a technology that is used to analyze the physical and chemical characteristics of particles in a fluid as it passes through at least one laser. Cell components are fluorescently labeled and then excited by the laser to emit light at varying wavelengths. CD4 and CD8 expression on thymocytes are positive selection of T cells in the thymus - the maturation of thymocytes can be followed by changes in expression of the CD4 and CD8 co-receptors. A two-color flow cytometric analysis of thymocytes using anti-CD4 and anti-CD8 antibodies, each tagged with a different fluorochrome, is illustrated. The %s of all thymocytes contributed by each major population are shown in the 4 quadrants. The least mature subset is the CD4/CD8 negative (double negative cells). Arrows indicate the series of maturation.

All chemokine receptors are...

GPCR (G protein coupled receptors)

Genetic basis of autoimmunity:

Genetic predisposition of autoimmune disease: - increased incidence in monozygotic than in dizygotic twins Multiple genes are associated with autoimmunity: - single gene mutations and mouse knockouts reveal critical pathways *MHC genes:* *- major genetic association with autoimmune diseases (relative risk of disease in individuals with particular HLA haplotypes)* - disease-associated alleles are present in normal individuals Non-MHC genes: - many loci identified by genome-wide association and linkage studies - most are found in intregenic regions; actual genes and their roles are unknown - recent discoveries in many genes and pathways

Autoimmunity:

Genome wide association studies are revealing genetic polymorphisms associated with autoimmune diseases Crohn's disease: - NOD-2: microbial sensor in intestinal epithelial and other cells - IL-23 receptor: involved in TH17 responses Rheumatoid arthritis, others: - PTPN-22 (tyrosine phosphatase): may control kinase-dependent lymphocyte activation Multiple sclerosis, others: - CD25 (IL-2 receptor): role in T cell activation and maintenance of regulatory T cells

Sources of allergens:

Grass and tree pollens, house dust mites, animal dander, nuts, fish, shell-fish, milk, eggs, insect venoms, mold/fungi *Allergens are predominantly proteins* Some people develop allergies to small molecules (drugs, chemicals, etc.)

Characteristics of adaptive immunity:

Highly specific Has to be primed first Slow process to acquire Has long lasting memory Non-reactive to self

Der p 2:

Homology to MD2, a human lipopolysaccharide (LPS), which can present LPS to TLR-4 Alta1 induces TLR-4 dependent innate immunity

Consequences of AIRE mutation..

Human disease: autoimmune polyendocrinopathy with candidiasis an ectodermal dysplasia (APECED), also called autoimmune polyendocrine syndrome (APS-1) - associated gene identified by positional cloning, named AIRE ("autoimmune regulator") Mouse knockout: autoantibodies against multiple organs, retina - failure to express many self antigens in the thymus => failure of negative selection

Consequences of AIRE mutation:

Human disease: autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), also called autoimmune polyendocrine syndrome (APS-1) - Associated gene identified by positional cloning, named AIRE ("autoimmune regulator") Mouse knockout: autoantibodies against multiple endocrine organs, retina - Failure to express many self antigens in the thymus = failure of negative selection

HMMER domain analysis:

Human genome interrogated for proteins with predicted chitin binding domains 7 candidates but only 4 that appeared logical from an immune signaling standpoint Silencing of LysMD3 transcripts results in significantly reduced pro-inflammatory cytokines secretion in human bronchial epithelial cells BEAS2B after stimulation with TLR ligands/chitin Silencing of LysMD4 transcripts results in enhanced IL-8 secre.on in human bronchial epithelial cells (BEAS2B) arer s.mula.on with TLR ligands and chitin Silencing of LysMD3 or IRAK1 transcripts results in significantly reduced IL8 secretion in human bronchial epithelial cells after Alternaria alternata spore challenge or in response to pure (NAG)7

Summary =

Humoral immunity is mediated by antibodies and is the effector arm of the adaptive immune system responsible for defense against extracellular microbes and microbial toxins. The antibodies that provide protection against infection may be produced by long-lived antibody-secreting cells generated by the first exposure to microbial antigen or by reactivation of memory B cells by the antigen. Antibodies block, or neutralize, the infectivity of microbes by binding to the microbes and sterically hindering interactions for the microbes with cellular receptors. Antibodies similarly block the pathologic actions of toxins by preventing binding of the toxins to host cells

The early steps of complement activation by the alternative, classical, and lectin pathways:

*Alternative pathway = activated by C3b binding to various activating surfaces, such as microbial cell walls* *Classical pathway = initiated by C1 binding to antigen-antibody complexes* *Lectin pathway = activated by binding of a plasma lectin to microbes* The C3b that is generated by the action of the C3 convertase binds to the microbial cell surface or the antibody and becomes a component of the enzyme that cleaves C5 (C5 convertase) and initiates the late steps of complement activation. The late steps of all three pathways are the same, and complement activated by all three pathways serves the same functions. The central event in complement activation is proteolysis of the complement protein C3 to generate biologically active products and the subsequent covalent attachment of a product of C3, called C3b, to microbial cell surfaces or to antibody bound to antigen.

Antibody isotypes:

*IgG* = opsonization of antigens for phagocytosis by macrophages and neutrophils - activation of the classical pathway of complement - antibody-dependent cell-mediated cytotoxicity mediated by natural killer cells - neonatal immunity: transfer of maternal antibodies across the placenta and gut - feedback inhibition of B cell activation *IgM* =activation of the classical pathway of complement - antigen receptor of naive B lymphocytes *IgA* = mucosal immunity: secretion of IgA into the lumens of the GI and respiratory tracts *IgE* = mast cell degranulation (immediate hypersensitivity reactions) *IgD* = antigen receptor of naive B lymphocytes

Il-4:

IL-4 is the signature cytokine of the TH2 subset and functions as both an inducer and an effector cytokine of these cells IL-4 stimulates B cell Ig heavy chain class switching to the IgE isotype IL-4 stimulates the development of TH2 effector cells from naive CD4+ T cells, and functions as an autocrine growth factor for differentiated TH2 cells IL-4, together with IL-13, contributes to an alternative form of macrophage activation that is distinct from the macrophage response to IFN-γ. IL-4 (and IL-13) stimulate peristalsis in the gastrointestinal tract, and IL-13 increases mucus secretion from airway and gut epithelial cells. IL-4 and IL-13 stimulate the recruitment of leukocytes, notably eosinophils

Structure of LysMD3:

ITIMs (immunoreceptor tyrosine-based inhibition motif) are phosphorylation motifs found in a large number of receptors or adaptor proteins The majority of these receptors are involved in regulation of the immune system Phosphorylated ITIMs recruit tyrosine phosphatases Although signaling through ITIM-bearing receptors is usually inhibitory, exceptions have been described

Effector functions of mucosal antibodies:

IgA antibodies are not good mediators of inflammatory reactions - complement activation - neutrophil chemotaxis - phagocytosis Immune exclusion/serve "escort" functions Beneficial not to induce inflammation Intra-epithelial virus neutralization by IgA Excretory function for IgA *IgA serve to export proteins, not good mediators of inflammation --> beneficial not to induce inflammation in the gut*

Key players in immediate reactions:

IgE bound via FcεRI to mast cells and basophils - mediator release

Central and peripheral tolerance to self antigens:

Immature lymphocytes specific for self antigens may encounter these antigens in the generative (central) lymphoid organs and are deleted, change their specificity (B cells only), or (in the case of CD4+ T cells) develop into regulatory lymphocytes (central tolerance). Some self-reactive lymphocytes may mature and enter peripheral tissues and may be inactivated or deleted by encounter with self antigens in these tissues or are suppressed by the regulatory T cells (peripheral tolerance).

Central and peripheral tolerance to self antigens:

Immature lymphocytes specific for self antigens may encounter these antigens in the generative (central) lymphoid organs and are deleted, change their specificity (only in B cells), or (in the case of CD4+ T cells) develop into regulatory lymphocytes - central tolerance. Some self-reative lymphocytes may mature and enter peripheral tissues and be inactivated or deleted by encounter with self antigens in these tissues, or are suppressed by the regulatory T cells (peripheral tolerance).

Central tolerance:

Immature self-reactive lymphocytes that recognize self antigens are eliminated in lymphoid organs (bone marrow, thymus) by apoptosis or other fates

Time course of allergic reactions:

Immediate reaction: - onset within seconds due to preformed or rapidly synthesized mediators - vascular permeability - contraction of smooth muscle Late phase: - induced synthesis and release of mediators - recruitment of eosinophils and TH2 lymphocytes - second phase of smooth muscle contraction - sustained edema, airway hyper-reactivity

Central tolerance: fates of immature self-reactive lymphocytes

Induced by antigen in generative lymphoid organs (thymus for T cells, bone marrow for B cells), and high-affinity recognition of the antigens Immature lymphocytes undergo apoptosis upon encounter with antigens (negative selection) - eliminates high-affinity self-reactive lymphocytes, which are potentially the most dangerous **Some self-reactive T cells that encounter self antigens in the thymus, develop into regulatory T cells, and immature B cells in the bone marrow change their receptors (rendered harmless)**

T cell differentiation:

Induction = cytokines act on T cells stimulated by antigen and co-stimulators to induce the transcription of cytokine genes that are characteristic of each subset Commitment = with continued activation, epigenetic modifications result in that subset's cytokine genes being fixed in a transcriptionally active state. Conversely, genes that encode cytokines not produced by that subset remain inactive. Because of these changes, the differentiating T cell becomes progressively committed to one specific pathway. Amplification = cytokines produced by any given subset promote the development of this subset and inhibit differentiation toward other CD4+ subpopulations. The net result is the accumulation of cells of one subset.

Strategies for delivery of vaccine into O-MALT:

Inert particular carriers: - Biodegradable copolymers - Immune-stimulating complexes (ISCOMs) - Hydroxyapatite crystals Live vaccine vectors (recombinant): - Vaccinia virus - Salmonella - Mycobacterium bovis

DTH:

Inflammation, consisting of leukocyte recruitment and activation, accompanies many of the reactions of CD4+ T lymphocytes and may damage normal tissues. This T cell-dependent injurious reaction is called *delayed-type hypersensitivity (DTH)*, the term hypersensitivity referring to tissue damage caused by an immune response. DTH frequently occurs together with protective cell-mediated immunity against microbes and may be the cause of much of the pathology associated with certain types of infection.

Reactions of CD4+ T cells in cell-mediated immunity:

*Induction of response:* CD4+ T cells recognize peptides that are derived from protein antigens and presented by dendritic cells in peripheral lymphoid organs. The T lymphocytes are stimulated to proliferate and differentiate into effector (and memory) cells, which enter the circulation. *Migration of effector T cells and other leukocytes to the site of antigen:* Effector T cells and other leukocytes migrate through blood vessels in peripheral tissues by binding to endothelial cells that have been activated by cytokines produced in response to infection in these tissues. *Effector functions of T cells:* Effector T cells recognize the antigen in the tissues and respond by secreting cytokines that recruit more leukocytes and activate phagocytes to eradicate the infection.

T cell differentiation:

*Induction* - cytokines act on T cells stimulated by antigen and co-stimulators to induce the transcription of cytokine genes that are characteristic of each subset *Commitment* - with continued activation, epigenetic modifications result in that subset's cytokine genes being fixed in a transcriptionally active state. Conversely, genes that encode cytokines not produced by that subset remain inactive. Because of these changes, the differentiating T cell becomes progressively committed to one specific pathway *Amplification* - Cytokines produced by any given subset promote the development of this subset and inhibit differentiation toward other CD4+ subpopulations. The net result is the accumulation of cells of one subset. One of the most important discoveries in immunology has been the identification of populations of CD4+ effector T cells that can be distinguished by the cytokines they produce and the transcription factors they express

Phases of T cell responses:

- Antigen recognition - Lymphocyte activation - Proliferation - Differentiation (effector or memory) - Effector functions (CD4 = activation of macrophages, B cells and other cells, and inflammation; CD8 = killing of infected cells and macrophage activation) Antigen recognition by T cells induces cytokine (e.g., IL-2) secretion particularly in CD4+ T cells, clonal expansion as a result of cell proliferation, and differentiation of the T cells into effector cells or memory cells. In the effector phase of the response, the effector CD4+ T cells respond to antigen by producing cytokines that have several actions, such as the recruitment and activation of leukocytes and activation of B lymphocytes, while CD8+ CTLs respond by killing other cells.

T helper cells --> differentiation of CD8+ T lymphocytes

- CD4+ helper T cells produce cytokines that stimulate CTL differentiation - CD4+ helper T cells also enhance the ability of APCs to stimulate CTL differentiation

Dendritic cells:

- Capture antigens in tissues - Transport to secondary lymphoid organs - Process and present to T cells - An essential link between innate and adaptive immunity

Strategies for enhancing mucosal immune response:

- Co-delivery with cytokines - Co-immunogens (Cholera toxin) - Peptides presented with potent T-cell epitopes

T cell can only survive if it can recognize weakly its own MHC complex:

- Ensures that only the T cells that can recognize self MHC can survive - Differentiate into CD4+ or CD8+ - Single-positive T cells If T cell passes positive selection (low-affinity/avidity recognition of peptide-MHC complex on thymic epithelial cell), it is rescued from programmed cell death and converted into a single positive T cell Lack of positive selection (failure to recognize peptide-MHC complex on thymic epithelial cell) leads to apoptotic cell death

Roles of T helper 2 (TH2) cells:

- IgE antibody production - autocrine induction of TH2 cells - alternative macrophage activation (by secreting IL-4 and IL-13) - activation of eosinophils - mucus secretion

IL4:

- Is the signature cytokine of the TH2 subset and functions as both an inducer and an effector cytokine of these cells - Stimulates B cell Ig heavy chain class switching to the IgE isotype - Stimulates the development of TH2 effector cells from naive CD4+ T cells, and functions as an autocrine growth factor for differentiated TH2 cells - Contributes to an alternative form of macrophage activation is distinct from the macrophage response to IFN-gamma...IL-4 and IL-13 suppress IFN-γ-mediated classical macrophage activation and thus inhibit defense against intracellular microbes.

Maturation of dendritic cells:

- Loss of endocytic and phagocytic receptors - Increased expression of MHC (Phagocytic/endocytic function declines, APC function improves with maturation) - Upregulation of co-stimulatory molecules (CD80 and CD86) required for T cell stimulation - Upregulation of CD40 and adhesion molecules ICAM-1 and LFA-3 - Fc receptors (endocytosis) decrease

Epigenetic mechanisms include:

- Methylation of DNA on certain cytosine residues that generally silence genes - Post-translational modifications of the histone tails of nucleosomes (e.g. acetylation, methylation, ubiquitination) that may render genes either active or inactive - active remodeling of chromatin by protein machines called remodeling complexes that can also either enhance or suppress gene expression - Silencing og gene expression by non-coding RNAs

Role of CD40 in T-cell activation:

- Naive T cells are activated by peptide-MHC complexes on activated APCs. - Antigen recognition by T cells together with some co-stimulation induces the expression of the CD40 ligand (CD40L) on the activated T cells. - CD40L engages CD40 on the APCs and may stimulate the expression of more B7 molecules and the secretion of cytokines that activate T cells. - *Thus, CD40L on the T cells makes the APCs better at promoting and amplifying T cell activation.*

Types of allergens:

- Non-infectious environmental substance that can induce IgE production thereby sensitizing the subject so that re-exposure causes an allergic reaction. Type I hypersensitivity. - Non-infectious environmental substance that can induce adaptive immune response in absence of IgE (ex. poison ivy). Type IV hypersensitivity.

B lymphocytes:

- Produce antibodies - Activate T cells Functions of antibodies = Neutralization of microbe, phagocytosis, complement activation

Significance of mucosal immunity:

- Protection from microbial colonization (adherence) - Prevention of environmental sensitization - Focus of much vaccine work - May have regulatory influence on systemic immunity - May block allergic sensitization

G protein-coupled receptors (GPCRs) are:

- Receptors that function by activating associated GTP-binding - Polypeptides that traverse the plasma membrane 7 times, because of which they are sometimes called serpentine receptors - Able to initiate downstream signaling events - Are relevant to immunity and inflammation; include receptors for leukotrienes, prostaglandins, histamine, complement fragments C3a and C5a, bacterial formyl peptides, and all chemokines **All chemokine receptors are GPCRs**

Phases of adaptive immune response:

- Recognition of antigens (with help from innate immunity) - Activation of lymphocytes - Proliferation (clonal expansion) - Differentiation into effector or memory B/T cells - Effector phase (elimination of antigens) - Return to homeostasis to avoid tissue damage from chronic inflammation

The mechanisms that make genes available or unavailable in chromatin are considered to be epigenetic mechanisms. These include:

- The methylation of DNA on certain cytosine residues that generally silences genes - Post-translational modifications of the histone tails of nucleosomes (ex. acetylation, methylation, and ubiquitination) that may render genes either active or inactive depending on the histone modified and the nature of the modification - Active remodeling of chromatin by protein machines called remodeling complexes that can also either enhance or suppress gene expression - Silencing of gene expression by non-coding RNAs

Summary roles of effector TH1 cells:

- activation of macrophages and other innate cells (neutrophils) - activation of B cells and complement - autocrine activation of T cells - endothelium activation

Roles of TH1 cells-- activation of macrophages and B cells:

- classical macrophage activation (enhanced microbial killing) - complement binding and opsonizing IgG antibodies

Infections trigger autoimmune reactions:

- clinical prodromes, animal models - autoimmunity may develop after infection is eradicated (ie. the autoimmune disease is predicted by infection but is not directly caused by the infection) - some autoimmune diseases are prevented by infections (type 1 diabetes, multiple sclerosis, others? -- increasing incidence in developed countries): mechanism unknown; similar protection suggested for asthma - The "hygiene hypothesis"

GI system:

- goblet cells - villus - intraepithelial lymphocytes - crypt - panth cells (anti-microbial peptides) - M-cells - Mucus - Peyer's patch - plasma cells Peyer's patches contain macrophages, dendritic cells, B-lymphocytes, and T-lymphocytes. Peyer's patches include a follicle within them Goblet cells can produce mucus Crypts increase the surface area of the gut IgA antibodies can label bacteria for transport without causing a huge inflammatory efflux

Opsonization:

- opsonization of microbe by IgG - binding of opsonized microbes to phagocyte Fc receptors - Fc receptor signals activate phagocyte - phagocytosis of microbe - killing of ingested microbe Antibodies of certain IgG subclasses bind to microbes and are then recognized by Fc receptors on phagocytes. Signals from the Fc receptors promote the phagocytosis of the opsonized microbes and activate the phagocytes to destroy these microbes.

Mechanisms of T cell anergy:

- recognition of self antigen without co-stimulation - engagement of inhibitory receptors Both cause signaling blocks --> unresponsive (anergic) T cell

Functions of complement:

1 = phagocytosis of microbes: Cell-bound C3b is an opsonin that promotes phagocytosis of coated cells 2 = recruitment and activation of leukocytes by C5a and C3a/ destruction of microbes by leukocytes: The proteolytic products C5a, C3a, and (to a lesser extent) C4a stimulate leukocyte recruitment and inflammation 3 = osmotic lysis of bacteria: The MAC lyses cells

Summary: Roles of effector TH1 cells:

1. Activation of macrophages and other innate cells (neutrophils) 2. Activation of B cells and complement 3. Autocrine activation of T cells 4. Endothelium activation

Role of T helper 2 (TH2) cells:

1. IgE antibody production 2. Autocrine induction of TH2 cells 3. Alternative macrophage activation 4. Activation of eosinophils 5. Mucus secretion CD4+ T cells that differentiate into TH2 cells secrete IL-4, IL-5, and IL-13. IL-4 (and IL-13) act on B cells to stimulate production of antibodies that bind to mast cells, such as IgE. Help for antibody production may be provided by TFH cells that produce TH2 cytokines and reside in lymphoid organs, and not by classical TH2 cells. IL-4 is also an autocrine growth and differentiation cytokine for TH2 cells. IL-5 activates eosinophils, a response that is important for defense against helminthic infections. IL-4 and IL-13 are involved in immunity at mucosal barriers, induce an alternative pathway of macrophage activation, and inhibit classical TH1-mediated macrophage activation.

CD4+ effector T-cells:

The functions of CD4+ effector T cells are to recruit and activate phagocytes (macrophages and neutrophils) and other leukocytes that destroy intracellular and some extracellular microbes, and to help B lymphocytes produce antibodies. CD4+ T lymphocytes are critical for phagocyte-mediated elimination of microbes, whereas CD8+ effector cells are responsible for the eradication of microbes, typically viruses, that infect and replicate inside all cells, including non-phagocytic cells For historical reasons, cell-mediated immunity refers to the process of CD4+ T cell-stimulated phagocyte-mediated killing of microbes Effector CD4+ T cells are generated by antigen recognition in secondary lymphoid organs but most of them leave these organs and migrate to peripheral sites of infection, where they function in microbe elimination.

Molecular events in follicular helper T cell generation:

The generation of TFH cells requires sequential activation of T cells, first by dendritic cells and then by activated B cells. The differentiated TFH cells migrate into germinal centers, where they activate B cells.

Molecular events in follicular helper T cell generation:

V(D)J Recombination:

The genes that encode diverse antigen receptors of B and T lymphocytes are generated by the rearrangement in individual lymphocytes of different variable (V) region gene segments with diversity (D) and joining (J) gene segments. A novel rearranged exon for each antigen receptor gene is generated by fusing a specific distant upstream V gene segment to a downstream segment on the same chromosome. This specialized process of site-specific gene arrangement is called V(D)J recombination. First, D and J are joined Then, V joins DJ

Germinal centers in secondary lymphoid organs:

The germinal center reaction in a lymph node: Activated B cells migrate into the follicle and proliferate, forming the dark zone of the germinal center. These B cells undergo extensive isotype switching and somatic hypermutation of Ig V genes, and migrate into the light zone, where they encounter follicular dendritic cells displaying antigen and TFH cells. B cells with the highest affinity Ig receptors are selected to survive, and they differentiate into antibody-secreting cells and memory B cells. The antibody-secreting cells leave and reside in the bone marrow as long-lived plasma cells, and the memory B cells enter the recirculating lymphocyte pool.

Homing properties of intestinal lymphocytes:

The gut-homing phenotype of IgA-producing B cells and effector T cells is imprinted by dendritic cells through the action of retinoic acid during the process of T cell activation

Humoral immunity functions:

The main functions of antibodies are to neutralize and eliminate infectious microbes and microbial toxins - neutralization of microbes and toxins - opsonization and phagocytosis of microbes - antibody-dependent cellular cytotoxicity Complement activation: - phagocytosis of microbes opsonized with complement fragments (ex, C3b) - inflammation - lysis of microbes

Humoral immunity:

The main functions of antibodies are to neutralize and eliminate infectious microbes and microbial toxins - neutralization of microbes and toxins - opsonization and phagocytosis of microbes - antibody-dependent cellular cytotoxicity Complement: - phagocytosis of microbes opsonized with complement fragments (ex. C3b) - inflammation - lysis of microbes

Functions of complement:

The major functions of the complement system in host defense: - Cell-bound C3b is an opsonin that promotes phagocytosis of coated cells --> phagocytosis of microbe - The proteolytic products C5a, C3a, and C4a stimulate leukocyte recruitment and inflammation --> recruitment and activation of leukocytes by C5a, C3a, and (to a lesser extent) C4a --> destruction of microbes by leukocytes - The MAC lyses cells --> osmotic lysis of bacteria

Which of the following statements about negative selection during lymphocyte development is most accurate?

The mechanism of negative selection is apoptosis actively induced by antigen-receptor recognition of self-antigens

Fungal allergic airway disease:

The prevalence of fungal allergy may be as high as 20% Specifically, 19% of respiratory patients respond to at least one fungal allergen extract via skin tests, while more than 66% of these patients respond to Alternaria

Steps in CTL-mediated lysis of target cells:

The process of CTL-mediated killing of targets consists of antigen recognition, activation of the CTLs, delivery of the lethal hit that kills the target cells, and release of CTLs

T cell activation:

The process of T cell activation generates, from a small pool of naive lymphocytes specific for an antigen, a large number of effector cells with the same specificity that function to eliminate that antigen and a population of long-lived memory cells that can rapidly react against the antigen in case it is reintroduced.

Domains of Ig and TCR proteins:

The relationships between the Ig and TCR gene segments and the domain structure of the antigen receptor polypeptide chains are indicated. The V and C regions of each polypeptide are encoded by different gene segments. The locations of intrachain and interchain disulfide bonds (S-S) are approximate. Areas in the dashed boxes are the hypervariable (complementarity-determining) regions. In the Ig μ chain and the TCR α and β chains, transmembrane (TM) and cytoplasmic (CYT) domains are encoded by separate exons. Light chains do not contain a D segment.

Summary (pt. 2):

The surface molecules whose expression is induced on T cell activation include proteins that are involved in retention of T cells in lymphoid organs, growth factors for cytokines, effector and regulatory molecules, and molecules that influence migration of the T cells. *Shortly after activation, T cells produce the cytokine IL-2 and express high levels of the functional IL-2 receptor. IL-2 drives the proliferation of the cells, which can result in marked expansion of antigen-specific clones.* Some activated T cells may differentiate into memory cells, which survive for long periods and respond rapidly to antigen challenge. *The maintenance of memory cells is dependent on cytokines such as IL-7, which may promote the expression of anti-apoptotic proteins and stimulate low-level cycling*. Memory T cells are heterogenous and consist of populations that differ in migration properties and functional responses. T cell responses decline after elimination of the antigen, thus returning the system to rest. The decline is largely because the signals for continued lymphocyte activation are also eliminated.

Clonal expansion:

The ~10,000-100,000 fold increase in the number of lymphocytes specific for an antigen that results from antigen stimulation and proliferation of naive T cells. Clonal expansion occurs in lymphoid tissues and is required to generate enough antigen-specific effector lymphocytes from rare naive precursors to eradicate infections

T cell precursors are in bone marrow

They migrate and mature in the thymus

Transport of IgA across epithelial cells:

Transcytosis

IgM antibodies:

When a naive B cell is first activated, they mainly make IgM antibodies IgM antibodies are very good at activating the complement cascade - *fixing complement.*

Humoral immunity:

Extracellular microbes activate B lymphocytes which secrete antibodies -- block infections and eliminate extracellular microbes

Pathways of apoptosis:

Apoptosis is induced by the mitochondrial and death receptor pathways, which culminate in fragmentation of the dead cell and phagocytosis of apoptotic bodies

Ig gene expression:

Primary RNA transcript Messenger RNA (mRNA) Nascent polypeptide Mature polypeptide Assembled Ig molecule

Role of T helper 17 (Th17) cells:

*1. Increased neutrophil responses* 2. production of anti-microbial peptides 3. increased barrier function

Role of CR2 and Toll-like receptors in B cell activation:

*B cell activation is facilitated by the CR2/CD21 co-receptor on B cells, which recognizes complement fragments covalently attached to the antigen or that are part of immune complexes containing the antigen* Complement activation is typically seen with microbes, which activate this system in the absence of antibodies by the alternative and lectin pathways, and by the classical pathway in the presence of antibodies. In all of these situations, complement fragments are generated that bind to the microbes *One of these fragments, called C3d, is recognized by the complement receptor (CR2, also called CD21), which enhances the strength of BCR signaling and thus functions as a co-receptor for B cells* Image: In immune responses to microbes, activation of B cells through the BCR may be enhanced by complement-coated antigen that can ligate both the BCR and complement receptor 2 (CR2) (A), and also by the simultaneous activation of Toll-like receptors (TLRs) on B cells by molecules (pathogen-associated molecular patterns [PAMPs]) derived from the microbe (B).

Role of CR2 and Toll-like receptors in B cell activation:

In the cannonical NF-κB signaling pathway downstream of the TNF receptor, TLRs, and antigen receptors, what role does IκB kinase (IKK) complex play?

*C. Activated IKK phosphorylates IκBα, which leads to IκBα degradation, allowing NF-κB to enter the nucleus* NF-κB is kept in the cytoplasm by bound IκBα. The function of the IKK complex is to remove IκBα, allowing NF-κB to enter the nucleus and promote the transcription of proinflammatory genes. IKK must be activated by TRAF signals generated originating from cell surface receptors. This leads to activation of the IKKβ subunit of IKK which phosphoryaltes IκBα. Phosphorylated IκBα is then ubiquitinated and degraded by the proteasome.

It has been postulated that regulatory T cells reduce available B7 co-stimulators on APCs, an this is one possible mechanism by which the Tregs inhibit immune responses. Which of the following molecules is expressed on regulatory T cells (Tregs) and functions to block B7-mediated co-stimulation?

*CTLA-4* Treg express CTLA-4, and CTLA-4 is a high affinity receptor for B7-1 and B7-2. Treg function depends on CTLA-4, and it is likely that one mechanism of Treg suppression of effector T cell responses is to competitively bind B7-1 and B7-2 on dendritic cells presenting self antigens to naïve T cells, or remove B7 molecules from these APCs. This results in reduced costimulation, which would prevent the induction of effecive immune responses.

Mechanisms of unresponsiveness to self antigens:

*Central tolerance:* Immature self-reactive lymphocytes that recognize self antigens are eliminated in lymphoid organs by apoptosis or other fates *Peripheral tolerance:* Mature self-reactive lymphocytes that recognize self antigens in peripheral tissues are inactivated (functional unresponsiveness = anergy), killed (apoptosis = deletion), or suppressed (blocks response) Anergy = functional unresponsiveness Deletion = apoptosis Suppressed = block in activation *"Clonal ignorance"*: Mature self-reactive lymphocyte clones do no encounter or respond to self antigens In normal individuals it is not known which self antigens induce tolerance by which mechanism

Macrophage activation: classical and alternative -

*Classically activated macrophage (M1)* - microbicidal actions: phagocytosis and killing of many bacteria and fungi - increased inflammation *Alternatively activated macrophage (M2)* - anti-inflammatory effects - wound repair, fibrosis (Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process)

Which of the following is an example of a GPCR? A) T cell antigen receptor (TCR) B) The B cell antigen receptor (BCR) C) CD4 D) Interlukin-2 (IL-2)receptor E) Chemokine receptor CCR7

*E. Chemokine receptor CCR7* *All chemokine receptors (including CCR7) are GPCRs.* The lymphocyte antigen receptors (TCR, BCR), CD4, and IL-2 receptor signal via associated proteins or non-receptor tyrosine kinases.

How do gram-positive bacteria and some fungi evade the complement system?

*Express thick walls that prevent the binding of complement proteins, such as MAC*

FasL:

*FasL on CTLs interacts with Fas on target cells, causes apoptosis of the target cell* CTLs kill target cells by two main mechanisms. 1, Complexes of perforin and granzymes are released from the CTL by granule exocytosis and enter target cells. The granzymes are delivered into the cytoplasm of the target cells by a perforin-dependent mechanism, and they induce apoptosis. 2, *FasL is expressed on activated CTLs, engages Fas on the surface of target cells, and induces apoptosis.* The major cytotoxic proteins in the granules of CTLs (and NK cells) are granzymes and perforin

IgA antibodies:

*IgA blocks adherence of bacteria to the mucosa and also facilitates opsonization through binding to Fc alpha receptors on phagocytic cells* IgA class switching the gut occurs by both T-dependent and T-independent mechanisms. In T-dependent IgA class switching, dendritic cells in the subepithelial dome of Peyer's patches capture bacterial antigens delivered by M cells and migrate to the interfollicular zone, where they present antigen to naive CD4+ T cells. The activated T cells differentiate into helper T cells with a T follicular helper phenotype and engage in cognate interactions with antigen-presenting IgM+IgD+ B cells that have also taken up and processed the bacterial antigen. B cell class switching to IgA is stimulated through T cell CD40L binding to B cell CD40, together with the action of TGF-β. This T cell-dependent pathway yields high-affinity IgA antibodies. T-independent IgA class switching involves dendritic cell activation of IgM+IgD+ B cells, including B-1 cells. TLR ligand-activated dendritic cells secrete cytokines that induce IgA class switch, including BAFF, APRIL, and TGF-β.

Continued..

*Junctional diversity* is caused by deletions and additions of base pairs between V, D, and J segments during somatic recombination, resulting in new junctional sequences not present in the germline. This accounts for the majority of Ig and TCR diversity. *Combinatorial diversity* is the second major mechanism for diversity, based on the large number of different V, D, and J segments inserted in the germline that can be used during somatic recombination, but it contributes much less to diversity than does junctional variability. *Somatic mutation* of variable genes occurs during the germinal center reaction in B cells only, and its impact on diversity is far less than the mechanism of junctional diversity. *Isotype switching (of Ig molecules only)* changes the non-antigen-binding region and does not contribute to diversity of antigen receptor specificity. *Polymorphism* refers to the presence of different alleles of a gene in the population, not in an individual, and is not a mechanism of diversity of the antigen receptor repertoires

Among the genes that are associated with common autoimmune diseases, the strongest associations are with which of the following?

*MHC genes* MHC genes, mainly class II MHC genes, are the most strongly associated with autoimmune disease

Which pair of molecules are found in cytotoxic T lymphocyte (CTL) granules and are important for CTL killing of target cells?

*Perforin and granzyme B* Perforin and granzyme B are the CTL granule constituents of most importance in killing of target cells. CTL granules are emptied by exocytosis into the intercellular space between the CTL and the target cell. Here, perforin polymerizes and inserts into the target cell plasma membrane and/or in the membranes of endocytic vesicles in the target cell. Granzyme B is a proteolytic enzyme that cleaves substrates in the cytoplasm of the target cell, leading to a cascade of enzyme activation that ends in apoptosis. Granzyme B enters the target cell via a perforin-dependent mechanism.

Roles of effector CD8+ T cells:

*Perforin and granzymes are important for CTL killing of target cells* Granzyme B enters the target cell via perforin Perforin = aids in delivering contents of granules into the cytoplasm of target cell Granzymes = serine proteases, which activate apoptosis once in the cytoplasm of the target cell Granulysin =has antimicrobial actions and can induce apoptosis

What are M cells?

*Specialized intestinal epithelial cells that transport antigens or microbes into Peyer's patches* M cells are intestinal epithelial cells with short villi. They engage in transport of intact microbes or molecules across the mucosal barrier into gut-associated lymphoid tissues, such as Peyer's patches, where they are handed off to DCs.

Deletion (activation-induced cell death):

*Stimulation of T cells by self antigens triggers apoptosis by engagement of death receptors (death receptor pathway) or imbalanced expression of pro-apoptotic proteins (mitochondrial pathway)* Evidence for the importance of AICD in maintenance of self-tolerance: - mice with mutations in Fas or Fas ligand develop a lupus-like autoimmune disease - humans with mutations in Fas or enzymes involved in death receptor-induced apoptosis (caspases): the autoimmune lymphoproliferative syndrome (ALPS) - eliminating both death pathways in mice --> "spontaneous" systemic autoimmune disease

T lymphocytes:

*T helper cells (CD4+)*: produce cytokines, which subsequently activate effector cells Effector functions = release cytokines that lead to activation of macrophages, inflammation, activation (proliferation and differentiation) of T and B lymphocytes) *Cytotoxic T cells (CTL or CD8+)*: Kill infected cells Effector functions = killing of infected cells *Regulatory T cells (Treg)* = regulate T cell function

Properties of TH1, TH2, and TH17 subsets of CD4+ helper T cells:

*TH1:* - signature cytokines = IFN-gamma - immune reactions = macrophage activation, IgG production - host defense = intracellular microbes - role in diseases = autoimmune diseases, tissue damage associated with chronic infections *TH2:* - signature cytokines = IL-4, IL-5, IL-13 - immune reactions = mast cell and eosinophil activation, IgE production, alternative macrophage activation - Host defense = helminthic parasites - role in diseases = allergic diseases *TH17:* - signature cytokines = IL-17A, IL-17F, IL-22 - immune reactions = neutrophilic and monocytic inflammation - host defense = extracellular bacteria and fungi - role in disease = autoimmune inflammatory diseases

Mechanisms of action of CTLA-4:

*The T cell ligand binding B7 on a professional antigen-presenting cell is CD28* An alternative ligand for B7, present on activated T cells, is CTLA-4. ***B7 is expressed on APCs and binds to CD28 on T cells *** CTLA-4 on T cells can bind B7 and block binding to CD28 --> causes functional inactivation

Antigen adherence to M-cells:

- Adherence favors endocytosis and transcytosis - Adherent materials tend to evoke strong immune responses - Wide variety of pathogens adhere to M-cells - Mechanism of adherence is unclear - Many commensal microorganisms avoid adherence to M-cells *M cells capture bacteria from the gut lumen and deliver them and their antigens to dendritic cells and lymphocytes in the Peyer's patch*

Phases of T cell responses:

- Antigen recognition - Lymphocyte activation - Proliferation - Differentiation - Effector functions (CD4+ = activation of macrophages, B cells, and other cells, inflammation; CD8+ = killing of infected cells; macrophage activation) Recognition by T cells induces cytokine (e.g., IL-2) secretion, particularly in CD4+ T cells, clonal expansion as a result of cell proliferation, and differentiation of the T cells into effector cells or memory cells. In the effector phase of the response, the effector CD4+ T cells respond to antigen by producing cytokines that have several actions, such as the recruitment and activation of leukocytes and activation of B lymphocytes, while CD8+ CTLs respond by killing other cells.

Changes in surface molecules after T cell activation:

A, The approximate kinetics of expression of selected molecules during activation of T cells by antigens and costimulators are shown. The illustrative examples include a transcription factor (c-Fos), a cytokine (IL-2), and surface proteins. These proteins are typically expressed at low levels in naive T cells and are induced by activating signals. CTLA-4 is induced 1 to 2 days after initial activation. The kinetics are estimates and will vary with the nature of the antigen, its dose and persistence, and the type of adjuvant. B, The major functions of selected surface molecules are shown and described in the text.

The combination of TCR and co-stimulatory signals induces naive T cells to express IL-2 and high affinity IL-2 receptors. This results in which of the following functional responses by the T cell? A. Clonal expansion B. Interferon γ expression C. CD40 ligand expression D. Granule exocytosis E. Migration out of a lymph node

A. *clonal expansion* IL-2 is the major autocrine growth factor for T cells. Naive T cells express two chains of the IL-2 receptor which bind IL-2 with low affinity. Antigen and co-stimulatory signals induce IL-2 production and expression of a third chain (CD25) of the receptor, which increases the affinity for IL-2. The T cell thus enters the cell cycle in response to IL-2 signals, and undergoes several rounds of proliferation, thereby expanding the clone of T cells specific for the inciting antigen.

Deletion of self-reactive T cells in the thymus:

AIRE (autoimmune regulator) is a regulator of gene transcription that stimulates thymic expression of many self antigens which are largely restricted to peripheral tissues Discovered as the genetic cause of a human autoimmune disease (APS-1)

Differentiation of CD4 T helper cells

Activated CD4 T cell... IL-12 causes differentiation into *TH1* (secrete IFN-gamma) --> antigen presentation and cellular immunity IL-4 causes differentiation into *TH2* (secrete IL-4, IL-5, IL-13) --> humoral immunity and allergy TGF-beta and IL-6 cause differentiation into *TH17* (secrete IL-17A, IL-17F, IL-22) --> tissue inflammation

Fyn:

A Src family kinase that phosphorylates ITAMs in the cytoplasmic tails of B cell receptor complex proteins. On antigen-mediated cross-linking of the B cell receptor (BCR), the ITAMs of Igα and Igβ are phosphorylated by Src family kinases, including Fyn, Lyn, and Blk. This initiates the signaling cascade for B cell activation.

Major basic protein (MBP) =

A cationic protein found in eosinophil granules

*Bcl-2 (Bcl-2 family proteins):*

A family of partially homologous *cytoplasmic and mitochondrial membrane proteins that regulate apoptosis by influencing mitochondrial outer membrane permeability*. Members of this family can be pro-apoptotic (such as Bax, Bad, and Bak) or anti-apoptotic (such as Bcl-2 and Bcl-XL)

Specificity:

A fundamental characteristic of the T cell response, like all adaptive immune responses, is that it is highly specific for the antigen that elicits the response Both the initial activation of naive T cells and the effector phases of T cell-mediated adaptive immune responses are triggered by recognition of the antigen by the antigen receptors of T lymphocytes *T cells have specificity for peptide fragments, derived from protein antigens, which are bound to and displayed by self major histocompatibility complex (MHC) molecules.*

The mechanism of therapeutic co-stimulatory blockade:

A fusion protein of the extracellular portion of CTLA-4 and the Fc tail of an IgG molecule is used to bind to and block B7 molecules, thus preventing their interaction with the activating receptor CD28 and inhibiting T cell activation Antibodies that block the CTLA-4 and PD-1 inhibitory receptors are approved **CTLA-4 binds to B7 and prevents it from activating CD28

The mechanism of therapeutic co-stimulatory blockade:

A fusion protein of the extracellular portion of CTLA-4 and the Fc tail of an IgG molecule is used to bind to and block B7 molecules, thus preventing their interaction with the activating receptor CD28 and inhibiting T-cell activation. Antibodies that block the CTLA-4 and PD-1 inhibitory receptors are approved. IL-2 is a major growth stimulatory factors --> causes T cells to undergo proliferation

B cells:

Activation leads to proliferation of antigen-specific cells and their differentiation, generating antibody-secreting plasma cells and memory B cells A single B cell may, within a week, give rise to as many as 5000 antibody-secreting cells, which collectively produce more than 10^12 antibody molecules per day This tremendous expansion is needed to keep pace with rapidly dividing microbes

Positive selection:

A process called positive selection facilitates the survival of potentially useful lymphocytes, and this development event is linked to lineage commitment, the process by which lymphocyte subsets are generated. In the T cell lineage, positive selection ensures the maturation of T cells whose receptors recognize self MHC molecules.

Roles of TH1 cells-- mutual activation of macrophages and T cells

A, Macrophages are activated by CD40L-CD40 interactions and by IFN-γ expressed by TH1 cells and perform several functions that kill microbes, stimulate inflammation, and enhance the antigen-presenting capacity of the cells. B, The principal responses of macrophages activated by the classical activation pathway, and their roles in T cell-mediated host defense, are listed. Macrophages are also activated during innate immune reactions and perform similar functions.

Role of infections in the development of autoimmunity:

A, Normally, encounter of a mature self-reactive T cell with a self antigen presented by a costimulator-deficient resting tissue antigen-presenting cell (APC) results in peripheral tolerance by anergy. B, Microbes may activate the APCs to express costimulators, and when these APCs present self antigens, the self-reactive T cells are activated rather than rendered tolerant. C, Some microbial antigens may cross-react with self antigens (molecular mimicry). Therefore, immune responses initiated by the microbes may activate T cells specific for self antigens.

C3b:

Alternative pathway of complement activation. *An antibody-independent pathway of activation of the complement system that occurs when the C3b protein binds to microbial cell surfaces.* The alternative pathway is a component of the innate immune system and mediates inflammatory responses to infection as well as direct lysis of microbes.

T cell exhaustion:

Acute infection: antigen cleared Effector and memory CTL response = cytokine secretion, proliferation, target killing Chronic infection: antigen persists *T cell exhaustion* = no cytokine secretion, reduced proliferation, no target cell killing Exhausted CD8+ T cell will not signal for clearance of the pathogen, even when presented with an antigen

T cell exhaustion:

Acute infection: antigen cleared --> effector and memory CTL response: cytokine secretion, proliferation, target killing Chronic infection: antigen persists --> *T cell exhaustion: no cytokine secretion, reduced proliferation, no target cell killing*

Clinical presentation of allergic reactions:

Allergy against inhaled proteins Respiratory symptoms: - wheezing, rhinitis - conjunctivitis - asthma-mild to severe in all age groups Cutaneous and GI symptoms: - eczema - oral allergy syndrome

Conclusions:

Alta1 enters cells (and this entry appears to be associated with the membrane) Alta1 stimulates MCP-1 (CCL2), IL-8, and GRO a/b/g (CXCL1), cytokines involved in recruiting of neutrophils, monocytes, and even angiogenesis in the airways Alta1 appears to interact with TLR-4 in a novel manner

P-selectin =

An endothelial adhesion molecule stored in cytoplasmic granules

Anergic:

Anergy is a state of unresponsiveness to antigenic stimulation. Lymphocyte anergy (also called clonal anergy) is the failure of clone of B or T cells to react to antigens - a mechanism of maintaining immunological tolerance to self. Clinically, anergy describes the lack of T-cell-dependent cutaneous delayed type hypersensitivity reactions to common antigens.

Effector functions of antibodies:

Antibodies against microbes and their toxins neutralize these agents, opsonize them for phagocytosis, sensitize them for antibody-dependent cellular cytotoxicity, and activate the complement system... these various effector functions may be mediated by different antibody isotypes Antibodies are produced by plasma cells in secondary lymphoid organs and bone marrow, and antibodies perform their effector functions at sites distant from their production

Effector functions of antibodies:

Antibodies against microbes neutralize these agents, opsonize them for phagocytosis, sensitize them for antibody-dependent cellular cytotoxicity, and activate the complement system. These various effector functions may be mediated by different antibody isotypes. Antibodies are produced by plasma cells in secondary lymphoid organs and bone marrow, and antibodies perform their effector functions at sites distant from their production.

Antibody-dependent cell-mediated cytotoxicity:

Antibodies of certain IgG subclasses bind to cells (e.g., infected cells), and the Fc regions of the bound antibodies are recognized by an Fcγ receptor on NK cells. The NK cells are activated and kill the antibody-coated cells

Opsonization:

Antibodies of certain IgG subclasses bind to microbes and are then recognized by Fc receptors on phagocytes. Signals from the Fc receptors promote the phagocytosis of the opsonized microbes and activate the phagocytes to destroy these microbes.

Helminths:

Antibodies, eosinophils, and mast cells function together to mediate the killing and expulsion of some helminthic parasites *Helminths (worms) are too large to be engulfed by phagocytes, and their integuments are relatively resistant to the microbicidal products of neutrophils and macrophages* *They can, however, be killed by a toxic cationic protein, known as the major basic protein, present in the granules of eosinophils.* IgE antibodies and, to a lesser extent, IgG and IgA antibodies that coat helminths can bind to Fc receptors on eosinophils and cause the degranulation of these cells, releasing the basic protein and other eosinophil granule contents that kill the parasites.

Continued summary =

Antibody-coated (opsonized) particles are phagocytosed by binding of the Fc portions of the antibodies to phagocyte Fc receptors. There are several types of Fc receptors specific for different subclasses of IgG and for IgA and IgE antibodies, and different Fc receptors bind the antibodies with varying affinities. Attachment of antigen-complexed Ig to phagocyte Fc receptors also delivers signals that stimulate the microbicidal activities of phagocytes. The complement system consists of serum and membrane proteins that interact in a highly regulated manner to produce biologically active products. The three major pathways of complement activation are the alternative pathway, which is activated on microbial surfaces in the absence of antibody; the classical pathway, which is activated by antigen-antibody complexes; and the lectin pathway, which is initiated by circulating lectins binding to carbohydrates on pathogens. These pathways generate enzymes that cleave the C3 protein, and cleaved products of C3 become covalently attached to microbial surfaces or antibodies, so subsequent steps of complement activation are limited to these sites. All pathways converge on a common pathway that involves the formation of a membrane pore after the proteolytic cleavage of C5.

Lymphatic vessels are critical for transporting foreign antigens to lymph nodes:

Antigen capture and transport --> antigen presentation and initiation of T cell responses

Antigen recognition:

Antigen transport is effected by M-cells which occur over organize mucosa-associated lymphoid tissue (O-MALT) After antigen stimulation, effector B lymphocytes leave O-MALT and migrate to distant mucosal or glandular sites M cells transport pathogens into Peyer's patches

Antigen presenting cells (APCs):

Antigen-presenting cells not only display antigens but also provide the stimuli that guide the magnitude and nature of the T cell response. These stimuli include surface molecules and secreted cytokines. Different types of APCs may express distinct signals that induce the development of different types of effector cells.

APCs:

Antigen-presenting cells not only display antigens, but also provide the stimuli that guide the magnitude and nature of the T cell response. These stimuli include surface molecules and secreted cytokines. Different types of APCs may express distinct signals that induce the development of different types of effector cells.

B cells, humoral immunity, and complement:

B cells and the antibodies they produce are part of the adaptive immune system. B cells must be activated before they can make antibodies. "Fail-safe" mechanisms help prevent inappropriate B cell activation, and the principle of clonal selection insures that only those B cells which make antibodies appropriate to defend against a pathogen are mobilized One billion B cells are produced each day The activation of B cells results in their proliferation, leading to clonal expansion, followed by differentiation, culminating in the generation of antibody-secreting plasma cells and memory B cells. Mature antigen-responsive B lymphocytes develop from bone marrow precursors before antigenic stimulation and populate peripheral lymphoid organs, which are the sites where lymphocytes interact with foreign antigens. Humoral immune responses are initiated by the recognition of antigens by specific B lymphocytes. Antigens bind to membrane immunoglobulin M (IgM) and IgD on mature, naive B cells and activate these cells.

B-cells:

B cells express surface immunoglobulin of a specificity created by that cell's particular immunoglobulin gene recombinations A totally different gene set encodes the T cell receptor for an antigen

Which of the following mechanisms contributes most to both Ig and TCR diversity?

B. *Changes in the nucleotide sequences at the junctions between recombined V, D, and J segments (junctional diversity)* Junctional diversity is caused by deletions and additions of base pairs between V, D, and J segments during somatic recombination, resulting in new junctional sequences that are not present in the germline. This accounts for the majority of Ig and TCR diversity. Combinatorial diversity is the 2nd major mechanism for diversity, based on the large number of different V, D, and J segments inserted in the germline that can be used during somatic recombination, but it contributes much less to diversity than does junctional variability. Somatic mutation of variable genes occurs during the germinal center reaction in B cells only, and its impact on diversity is far less than the mechanism of junctional diversity. Isotype switching (of Ig molecules only) changes the non-antigen-binding region and does not contribute to diversity of antigen receptor specificity. Polymorphism refers to the presence of different alleles of a gene in the population, not in an individual, and is not a mechanism of diversity of the antigen receptor repertoires.

In type 1 diabetes (insulin-dependent diabetes mellitus), the target of the autoimmune attack is:

B. *The beta-cells in the islets of Langerhans* The antigens such as glutamic acid decarboxylase (GAD) and insulin produced by the beta-cells are the target of this autoimmune attack.

Which of the following statement about negative selection during lymphocyte development is most accurate?

B. *The mechanism of negative selection is apoptosis is actively induced by antigen-receptor recognition of self antigens* Negative selection is a mechanism that promotes a self-tolerant lymphocyte repertoire for both B and T cells. It occurs in the generative lymphoid organs (bone marrow and thymus) when developing lymphocytes express antigen receptors that bind too strongly to self antigens. The major mechanism is actively induced apoptosis; immature lymphocytes that receive strong antigen receptor-mediated signals are particularly susceptible to death by apoptosis. Positive selection in the thymus promotes a self-MHC restricted T cell repertoire

Fos/Jun transcription factors:

Binds to the nuclear AP-1 site responsible for 90% of IL-2 enhancer activity. Activation protein (AP-1): A family of DNA-binding transcription factors composed of dimers of two proteins that bind to one another through a shared structural motif called a leucine zipper. The best-characterized AP-1 factor is composed of proteins Fos and Jun. AP-1 is involved in transcriptional regulation of many different genes that are important in the immune system, such as cytokine genes.

Requirements of protective vaccines:

Block adherence of microorganism to host Facilitate clearance from host Neutralize toxin Must recognize "virulence" epitopes Must be immunogenic Must not induce autoimmune disease Should induce long-lasting immunity Must induce the type of response that is effective to eliminate pathogen (eg. TH1 or TH2)

Distinct lineages of lymphocyte maturation:

Commitment to the B or T lineage depends on instructions received from several cell surface receptors, which induce specific transcriptional regulators that drive a common lymphoid progenitor to specifically assume a B cell or a T cell fate. The cell surface receptors and transcription factors that contribute to commitment induce expression of the proteins involved in antigen receptor gene rearrangements and make particular antigen receptor gene loci accessible to these proteins. - Developing B cells, the immunoglobulin (Ig) heavy chain locus, originally in an inaccessible chromatin configuration, is opened up so that is becomes accessible to the proteins that will mediate Ig gene rearrangement and expression - Developing αβ T cells, the T cell receptor (TCR) β gene locus is made available first Pluripotent stem cells give rise to distinct B and T cell lineages. Hematopoietic stem cells (HSCs) give rise to distinct progenitors for various types of blood cells. *One of these progenitor populations is called a common lymphoid progenitor (CLP). CLPs give rise mainly to B and T cells but may also contribute to NK cells and some dendritic cells.* Pro-B cells can eventually differentiate into follicular (FO) B cells, marginal zone (MZ) B cells, and B-1 cells. Pro-T cells may commit to either the αβ or γδ T cell lineages. Commitment to different lineages is driven by various transcription factors, ILC, innate lymphoid cells.

CR2:

Complement receptor type 2 (CR2). A receptor expressed on B cells and follicular dendritic cells that binds proteolytic fragments of the C3 complement protein, including C3d, C3dg, and iC3b. CR2 functions to stimulate humoral immune responses by enhancing B cell activation by antigens and by promoting the trapping of antigen-antibody complexes in germinal centers. *CR2 is also the receptor for Epstein-Barr virus*

Maturation of T cells:

Constant interaction between non-lymphoid cells and T cell precursors Signals form non-lymphoid cells help T precursors to develop 95% of T precursors die and fail to move out of the thymus

High endothelial venules (HEV):

Contain specialized endothelial cells lining post capillary venules Display organ-specific recognition sites called "vascular addressins" that are recognized by specific cell adhesion molecules on lymphocytes HEV cells are characterized by: - elongated shape and prominent glycocalyx on luminal surface - polarized, with a domed luminal surface separated from the basolateral surface by adherent junctions, not tight junctions - cells rest on basal lamina that constitutes the rate-limiting barrier to migrating lymphocytes

Spatial events of T cell functions:

Effector CD4+ T cells are generated by antigen recognition in secondary lymphoid organs but most of them leave these organs and migrate to peripheral sites of infection where they function in microbe elimination Expression of endothelial adhesion molecules and chemokines bind receptors on effector and memory T cells Differential expression of adhesion molecules and chemokine receptors on effector and memory T cells favor their migration into inflammatory sites

Sequential events of T cell function:

Effector and memory T cells enter peripheral tissues Antigen recognition by T cells Activated antigen-specific T cells are retained at site of infection and perform effector functions

Natural Killer (NK) cell:

Effector functions = killing of infected cells

Epigenetics mechanisms:

Epigenetics refers to mechanisms that control gene expression (as well as gene rearrangement in developing lymphocytes) that go beyond the actual sequence of DNA in individual genes DNA exists in chromosomes tightly bound to histones and non-histone proteins, forming what is known as chromatin. DNA in chromatin is wound around a protein core of histone octamers, forming structures called nucleosomes, which may be either well separated from other nucleosomes or densely packed.

PAMPs target TLRs and other PRRs:

Examples of pathogen associated molecular patterns: - LPS (TLR4) - Bacterial Flagellin (TLR5) - Peptidoglycan - dsRNA (TLR3) - Unmethylated GpG motifs (TLR9)

Danger theory:

Immune system does not distinguish between self and non-self Instead, immune system discriminated between what might cause damage Explained by Polly Matzinger in 1994 Recaps 65 years of immunological theory in one simple diagram

Cell-mediated immunity to Listeria monocytogenes:

Immunity to L. monocytogenes is measured by inhibition of bacterial growth in the spleens of animals inoculated with a known dose of viable bacteria. Such immunity can be transferred to normal mice by T lymphocytes but not by serum from syngeneic mice previously immunized with killed or low doses of L. monocytogenes. In an in vitro assay of cell-mediated immunity, the bacteria are actually killed by activated macrophages and not by T cells *T lymphocytes adoptively transfer specific immunity, but serum fails to transfer specific immunity. Only activated macrophages kill Listeria in vitro*

Summary pt. 1:

Immunologic tolerance is unresponsiveness to an antigen induced by the exposure of specific lymphocytes to that antigen. Tolerance to self antigens is a fundamental property of the normal immune system, and the failure of self-tolerance leads to autoimmune disease. Antigens may be administered in ways that induce tolerance rather than immunity, and this may be exploited for the prevention and treatment of transplant rejection, and autoimmune and allergic diseases. *Central tolerance* is induced in the generative lymphoid organs (thymus and bone marrow) when immature lymphocytes encounter self antigens present in these organs. *Peripheral tolerance* occurs when mature lymphocytes recognize self antigens in peripheral tissues under particular conditions. In T lymphocytes, central tolerance occurs when immature thymocytes with high-affinity receptors for self antigens recognize these antigens in the thymus. Some immature T cells that encounter self antigens in the thymus die (negative selection), and others develop into *FoxP3+ regulatory T lymphocytes* that function to control responses to self antigens in peripheral tissues.

HEV:

In O-MALT, HEVs are present in T cell areas between B cell follicles In D-MALT, venules have flat endothelial cells that share many features with HEVs HEVs produce sulfated glycolipids and glycoproteins into the vascular lumen (not known whether these products play a role in homing or extravasation)

Development of memory T cells:

In response to antigen and co-stimulation, naive T cells differentiate into effector and memory T cells. A, according to the linear model of memory T cell differentiation, most effector cells die and some survivors develop into the memory T cell population B, according to the branched differentiation model, effector and memory cells are alternative fates of activated T cells

Migration of B cells and helper T cells and T-B interaction:

The activation of specific B and T cells by the same antigen is essential for their functional interaction and brings them into proximity to enhance the likelihood of the antigen-specific B and T cells locating one another.

These dome-like structures are found in the small intestine. They are enriched in lymphoid tissue, making them key sites for coordinating immune responses to pathogens. They also help promote tolerance to harmless microbes and food...

Peyer's patches

Cell-mediated immunity:

Phagocytosed microbes in macrophage activate helper T lymphocytes - activate macrophages to kill phagocytosed microbes MHC II are found on macrophages, B cells, and dendritic cells - respond to extracellular challenges and present to CD4+ T cells ____________ Intracellular microbes (ex. viruses replicating within the cell) activate cytotoxic T lymphocytes - kill infected cells and eliminate reservoirs of infection MHC I are found on all nucleated cells - respond to intracellular challenges and present to CD8+ T cells

_____ of thymocytes is necessary to produce a T cell repertoire capable of interacting with self-MHC molecules:

Positive selection

Stages of lymphocyte maturation:

Precursor T cells = double negative (*Pro-T cells*) *Pre-T cells* = VDJ recombination and generation of pre-TCR (invariant pre-Ta and b chain) *Double-positive cells* - express CD4 and CD8 - start to express TCRab *Single-positive cells* - through position and negative selection

Summary:

Regional immune systems, including those in the gastrointestinal tract and skin, are specialized collections of innate and adaptive immune cells at particular anatomic locations, which perform protective and regulatory functions that are unique to those sites. The gastrointestinal immune system must cope with the presence of trillions of commensal bacteria in the gut lumen by preventing their invasion and tolerating their presence in the lumen, while also identifying and responding to numerically rare pathogenic organisms. Innate immunity in the gastrointestinal system is mediated by mucosal epithelial lining cells, which impede microbial invasion by tight intercellular junctions, secretion of mucus and production of anti-microbial molecules, such as defensins. Innate immune effector cells in the lamina propria include macrophages, dendritic cells, and mast cells. Intraepithelial lymphocytes, including γδ T cells, provide defense against commonly encountered microbes at the intestinal epithelial barrier.

Regulatory T cells:

Regulatory T cells are generated by self antigen recognition in the thymus (sometimes called natural regulatory cells) and (probably to a lesser extent) by antigen recognition in peripheral lymphoid organs (called inducible or adaptive regulatory cells). The development and survival of these regulatory T cells require IL-2 and the transcription factor FoxP3. In peripheral tissues, regulatory T cells suppress the activation and effector functions of other self-reactive and potentially pathogenic lymphocytes. ---- *Regulatory T cells are CD4+ cells that express high levels of CD25 (IL-2 receptor alpha chain)* Generated by self antigen recognition in the thymus or peripheral tissues Generation requires a transcription factor called Foxp3 (mutations in Foxp3 are the cause of a severe autoimmune disease in humans and mice)

Gram positive wall:

Relatively thick layer of peptidoglycan Regardless of thickness, peptidoglycan is permeable to numerous substances Teichoic acid component of peptidoglycan, composed of glycerol and phosphate Lipoteucholic acid is attached to the lipids of cytoplasmic membrane - gives cell a negative charge

Rational strategies for mucosal immunization:

Requirements: - Safe taken orally - Long-lasting due to continued maintenance of memory - Survive in gastric and intestinal environments - Must escape normal clearance mechanisms - Must compete for inclusion within M-Cell transport - Must arrive intact to antigen-processing cells - Must induce dimeric sIgA reactive with cell surface Ex. of mucosal immunization = influenza flu mist (nasal)

ITIM sequences in activating molecules:

SHP-2/PTPN11, SH2-containing protein tyrosine phosphatase-2 Phosphorylation of SHP-2 at Tyr542 and Tyr580 in response to growth factor receptor ac.va.on are thought to relieve basal inhibi.on and s.mulate SHP-2 tyrosine phosphatase activity

Modes of antigen sampling:

Stratified, non-keratinized or para-keratinized epithelia (oral cavity, pharynx, esophagus, urethra, vagina) - antigen sampling depends on dendritic cells -- ex. Langerhans cells, phagocytic, antigen-presenting motile "scouts" - Dendritic cells may then transport antigens to local and regional lymphoid follicles Connects MALT with pathogens outside of the epithelial barrier

Summary pt. 2:

Several mechanisms account for peripheral tolerance in mature T cells. In Cd4+ T cells, anergy is induced by antigen recognition without adequate co-stimulation or by engagement of inhibitory receptors such as CTLA-4 and PD-1. Regulatory T cells inhibit immune responses by multiple mechanisms. T cells that encounter self antigens without other stimuli or that are repeatedly stimulated may die by apoptosis. In B lymphocytes, central tolerance is induced when immature B cells recognize multivalent self antigens in the bone marrow. The result in the acquisition of a new specificity, called receptor editing, or apoptotic death of the immature B cells. Mature B cells that recognize self antigens in the periphery in the absence of T cell help may be rendered anergic and ultimately die by apoptosis or become functionally unresponsive because of the activation of inhibitory receptors. Autoimmunity results from a failure of self-tolerance. Autoimmune reactions may be triggered by environmental stimuli, such as infections, in genetically susceptible individuals.

Properties of TH1, TH2, and TH17 subsets of CD4+ helper T cells:

Signature cytokines: TH1 = IFN-gamma TH2 = IL-4, IL-5, IL-13 TH17 = IL-17A, IL-17F, IL-22

Modes of antigen sampling:

Simple epithelia (bronchiole, intestine, bronchi) - antigen sampling depends on M cells and trans-epithelial transport - dendritic cells may also participate in antigen transport Goblet cells produce mucus - important for trapping bacteria; important for clearance of bacteria, and preventing them from crossing the epithelium

Pathways of antigen delivery to follicular B cells:

Small antigens are delivered to B cells in follicles through afferent lymphatics and via conduits. Larger antigens are delivered by sub-capsular sinus macrophages or by dendritic cells in the medulla.

Generation of functional TCR:

Somatic recombination - not associated with meiosis - requires recombinases that can cleave DNA *RAG1 and RAG2 (recombination-activing gene)* = Create combinatorial diversity and junctional diversity *Changes in the nucleotide sequences at the junctions between recombined V, D, and J segments (junctional diversity) contributes most to both Ig and TCR diversity*

Which of the following characteristics is common to both T-cell receptors and immunoglobulins?

Somatic recombination of V, D, and J segments is responsible for the diversity of antigen binding sites

In immune responses to microbes, activation of B cells through the BCR may be enhanced by complement-coated antigen that can ligate both the BCR and complement receptor 2 (CR2), and also by the simultaneous activation of Toll-like receptors (TLRs) on B cells by molecules (pathogen-associated molecular patterns [PAMPs]) derived from the microbe...

Some non-microbial polysaccharides also activate complement by the alternative or lectin pathway, and this is one reason that such antigens are able to induce antibody responses without T cell help

Fungi..

Source of novel therapeutics and etiological agents of disease Fungi and their spores are ubiquitous and constitute the largest proportion of airborne biological particles

Molecular mimicry:

Specific epitope of an infectious agent mimics a host antigen and triggers self-reactive T-cell clone

Alta1 is the major secreted Alternaria allergen:

Specific to Alternaria with no predictable function Exhibits enzymatic activities - hydrolase (esterase), phosphatase >90% of sensitized patients have IgE for this protein**

Distinct B cell subsets mediate different types of antibody responses:

Spleen and other lymphoid organs: *Follicular B cells* = T-dependent, isotype-switched, high-affinity antibodies, long-lived plasma cells *Marginal zone B cells* = T-independent, mainly IgM, short-lived plasma cells Mucosal tissues: *B-1 cells* = T-independent, mainly IgM, short-lived plasma cells

Macrophage activation: classical and alternative -

Subsets of activated macrophages are shown. Different stimuli activate monocytes-macrophages to develop into functionally distinct populations. *Classically activated macrophages* are induced by microbial products and cytokines, particularly IFN-gamma (produced by TH1), and are microbicidal and involved in potentially harmful inflammation. *Alternatively activated macrophages* are induced by IL-4 and IL-13 (produced by TH2 cells and other leukocytes) and function to control inflammation--they may also promote tissue repair and fibrosis. There are two different subpopulations being studied in the context of cancer and inflammation --> classically activated/pro-inflammation (M1) and alternatively activated/pro-resolution (M2) M2 can help with tissue repair and have anti-inflammatory effects While M1 can kill cancer cells, M2 can increase vascularization and actually assist cancer cells (increasing immune response might not necessarily be beneficial unless you know specifically what cells you are activating)

Syk:

Syk A cytoplasmic protein tyrosine kinase, similar to ZAP-70 in T cells, that is critical for early signaling steps in antigen-induced B cell activation. Syk binds to phosphorylated tyrosines in the cytoplasmic tails of the Igα and Igβ chains of the BCR complex and in turn phosphorylates adaptor proteins that recruit other components of the signaling cascade.

Zika:

Symptoms = fever, rash, joint pain, conjunctivitis Since the Zika virus disease (Zika) outbreak began in Brazil in May 2015, the virus has spread to more than 20 countries. Zika virus is not currently circulating in the continental US, but cases have been reported in returning travelers. Zika virus is spread mainly by mosquitos (Aedes aegypti and Aedes albopictus)

Summary:

T cell responses are initiated by signals that are generated by TCR recognition of peptide-MHC complexes on the surface of an APC and through signals provided at the same time by co-stimulators expressed on APCs. The best-defined co-stimulators are members of the B7 family, which are recognized by receptors of the CD28 family (expressed on T cells). The expression of B7 co-stimulators on APCs is increased by encounters with microbes, providing a mechanism for generating optimal responses against infectious pathogens. Some members of the CD28 family inhibit T cell responses and the outcome of T cell antigen recognition is determined by the balance between engagement of activating and inhibitory receptors of this family. T cell responses to antigen and co-stimulators include changes in the expression of surface molecules, synthesis of cytokines and cytokine receptors, cellular proliferation and differentiation into effector and memory cells.

Summary...

T cells of the CD8+ subset proliferate and differentiate into cytotoxic T lymphocytes (CTLs), which express cytotoxic granules and can kill infected cells The differentiation of CD8+ T cells into functional CTLs and memory cells requires recognition of antigen presented by dendritic cells, signals from CD4+ helper T cells in some situations, co-stimulation, and cytokines. Differentiation to CTLs involves the acquisition of the machinery to kill target cells, and is driven by various transcription factors. In some situations of chronic antigen exposure (such as tumors and chronic viral infections), CD8+ T cells initiate a response but begin to express inhibitory receptors that suppress the response, a process called exhaustion.

Which cells become cytotoxic T cels?

T cells that express CD8

CD28:

T-cell ligand that binds the B7 on a professional antigen-presenting cells

Match the T cell population to its correct signature cytokines:

TH1 = IFN-gamma TH2 = IL-4, IL-5, IL-13 TH17 = IL-17A, IL-17F, IL-22

Roles of TH1 cells - activation of macrophages and B cells:

TH1 cells secrete IFN-γ, which acts on macrophages to increase phagocytosis and killing of microbes in phagolysosomes, and on B lymphocytes to stimulate production of IgG antibodies that opsonize microbes for phagocytosis. Help for antibody production may be provided not by classical TH1 cells, most of which migrate out of lymphoid organs to sites of infection and inflammation, but by follicular helper T (TFH) cells that remain in lymphoid organs and produce IFN-γ.

T cell populations:

TH1, TH2, and TH17 cells each have distinct patterns of homing, in large part defined by the chemokine receptors and adhesion molecules they express, which direct them to migrate into different sites of infection Many effector CD4+ T cells produce various combinations of cytokines or only some of the cytokines characteristic of a particular subset and are not readily classifiable into separable populations. For instance, in many inflammatory reactions, there may be T cells that produce both both IFN-γ (characteristic of TH1 cells) and IL-17 (typical of TH17 cells).

Role of T helper 17 cells:

TH17: - *Increased neutrophil responses* - Production of anti-microbial peptides - Increased barrier function

Oral tolerance:

The GI tract = largest immunologic organ Constantly exposed to a myriad of dietary & microbial antigens Very few develop food allergies - onset of oral tolerance Oral antigens are sampled by the intestinal mucosa Antigens might be taken up by Microfold cells (M-cells) overlying Peyer's patches, dendritic cells, or epithelial cells Different cells participate in the induction of oral tolerance. Among them, regulatory T cells being the most important Several factors, few related antigens and others inherent host related factors, influence induction of oral tolerance Disturbances of oral tolerance lead to food hypersensitivity

Phases of the humoral immune response:

The activation of B cells is initiated by specific recognition of antigens by the surface Ig receptors of the cells. Antigen and other stimuli, including helper T cells, stimulate the proliferation and differentiation of the specific B cell clone. Progeny of the clone may differentiate into plasma cells that produce IgM or switch to other Ig isotypes, may undergo affinity maturation, or may persist as memory cells.

Phases of humoral immune response:

The activation of B cells is initiated by specific recognition of antigens the surface Ig receptors of the cells. Antigen and other stimuli, including helper T cells, stimulate the proliferation and differentiation of the specific B cell clone Progeny of the clone may differentiate into plasma cells that produce IgM or other Ig isotypes (ex, IgG), may undergo maturation, or may persist as memory cells.

The early steps of complement activation by the alternative, classical, and lectin pathways:

The alternative pathway is activated by C3b binding to various activating surfaces, such as microbial cell walls The classical pathway is initiated by C1 binding to antigen-antibody complexes The lectin pathway is activated by binding of a plasma lectin to microbes The C3b that is generated by the action of the C3 convertase binds to the microbial cell surface or the antibody and becomes a component of the enzyme that cleaves C5 (C5 convertase) and initiates the late steps of complement activation. The late steps of all three pathways are the same, and complement activated by all three pathways serves the same functions. The central event in complement activation is proteolysis of the complement protein C3 to generate biologically active products and the subsequent covalent attachment of a product of C3, called C3b, to microbial cell surfaces or to antibody bound to antigen.

Conclusions (pt 3):

The diversity of the antibody and TCR repertoires is generated by the combinatorial associations of multiple germline V, D, and J gene segments and junctional diversity generated by the addition or removal of random nucleotides at the sites of recombination. These mechanisms generate the most diversity at the junctions of the segments that form the third hypervariable regions of both antibody and TCR polypeptides. B cell maturation occurs in stages characterized by different patterns of Ig gene rearrangement and expression. In the earliest B cell precursors, called Pro-B cells, Ig genes are initially in the germline configuration, and D to J rearrangement occurs at the Ig heavy chain locus.

Functions of co-stimulators:

The expression of B7 co-stimulators is regulated and ensures that T lymphocyte responses are initiated only when needed If the resting APC expresses few or no co-stimulators and fails to activate naive T cells --> no response or tolerance If microbes and cytokines produced during innate immune responses activate APCs to express co-stimulators such as B7 molecules, the APCs become capable of activating naive T cells --> T cell survival, proliferation, and differentiation. Activates APCs also produce cytokines such as IL-12, which stimulate the differentiation of naive T cells into effector cells.

Functions of co-stimulators:

The expression of B7 co-stimulators is regulated and ensures that T lymphocyte responses are initiated only when needed... The resting APC (typically dendritic cells presenting self antigens) expresses few or no costimulators and fails to activate naive T cells. (Antigen recognition without costimulation may make T cells unresponsive [tolerant]). *Microbes and cytokines produced during innate immune responses activate APCs to express costimulators, such as B7 molecules.* The APCs (usually presenting microbial antigens) then become capable of activating naive T cells. Activated APCs also produce cytokines such as IL-12, which stimulate the differentiation of naive T cells into effector cells.

CD4+ effector T cells:

The functions of CD4+ effector T cells are to recruit and activate phagocytes (macrophages and neutrophils) and other leukocytes and destroy intracellular and some extracellular microbes, and to help B lymphocytes to produce antibodies CD4+ T lymphocytes are critical for phagocyte-mediated elimination of microbes, whereas CD8+ effector cells are responsible for the eradication of microbes, typically viruses, that infect and replicate inside all cells, including non-phagocytic cells. Cell-mediated immunity refers to the process of CD4+ T cell-stimulate phagocyte-mediated killing of microbes

Alternaria:

Ubiquitous airborne fungus and prolific saprophyte Contains many plant pathogenic species Clinical association with allergy, severe life threatening asthma, chronic rhinosinusitis and invasive infection (rare)

Transcriptional regulation of Ig genes:

V-D-J recombination brings promoter sequences (shown as P) close to the enhancer (enh). The enhancer promotes transcription of the rearranged V gene (V2, whose active promoter is indicated by a bold green arrow). Many receptor genes have an enhancer in the J-C intron and another 3′ of the C region. Only the 3′ enhancer is depicted here.

Virus:

Viruses have evolved to use various cell surface molecules to gain entry into host cells and to use the host cell's genetic and protein synthetic machinery to replicate and disseminate from one cell to another Viruses can infect and survive in a wide variety of cells. The viruses cannot be destroyed if the infected cells lack intrinsic microbicidal mechanisms, or if the viruses are in the cytosol where they are inaccessible to these killing mechanisms. In those situations, the only way to eradicate the established infection is to kill the infected cell, releasing the virus from its home and crippling its ability to survive and replicate *This function of killing cells with viruses in the cytosol is mediated by CD8+ cytotoxic T lymphocytes (CTLs), the effector cells of the CD8+ lineage*

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