Immunology

Cluster of differentiation

CD, surface proteins used to define a specific cell type, expressed on different cells at different stages of differentiation

Antigen-Presenting Cells (APCs)

Capture, process, and display microbial particles (antigens) for lymphocyte activation ex) Dendritic Cells, macrophages, B cells

Phagocytes

Cells which ingest and destroy microbes, remove damaged cells ex) Neutrophils, Monocytes/Macrophages

Antibody-dependent Complement Activation

Classical Pathway- -Complement component C1 binds to Fc (constant) portion of Abs on microbial surfaces -ALl complement pathways converge with C3b depositing onto microbial surgaces, opsonizing the microbe and promoting phagocytosis -Effector functions of C3b: 1) Opsonizing microbe, phagocyte C3b receptor recognizes this and phagocytoses the microbe 2)Crb binds, formation of Membrane Attack Complex MAC, leading to osmotic lysis of microbe 3)complement can proteolyze to C5a, C4a, and C3a which recruit and activate leukocytes to destroy the microbe

Complement

Collection of circulating proteins that interact to modulate immune responses

Non-neutrophil Granulocytes

Contain cytoplasmic granules with various inflammatory and antimicrobial mediators

Opsonization

Decoration of targets to promote recognition by leukocytes

Cytokines

Dynamically secreted protein mediators that coordinate immune responses

Type 1 Hypersensitivity Reaction

Immediate Hypersensitivity -IgE mast cell mediated reaction resulting in allergy -certain individuals mount strong Th2 responses to antigens for unclear reasons -Process: Exposure to allergen (peptide), Ag is presented with MHC 2 to CD4 T cells, Ag activation of CD4 Th2 cells and stimulation of IgE class switching in B cells in Germinal Centers, production and secretion of IgE, binding of Fc portion of IgE to Fc receptors on mast cells called mast cell sensitization, on repeat exposure to allergen, we have activation of mast cell, release of histamines and cytokines -clinical manifestations include allergic rhinitis, food allergies, broncial asthma, anaphylaxis

Type III Hypersensitivity Reactions

Immune Complex Diseases -Ag-Ab complexes form in the circulation* possibly depositing in blood vessels, promoting complement activation and inflammation (leading to vasculitis) -Ex) Lupus

Phagocytosis

Ingestion of targets (microbes) for destruction

MHC

Major Histocompatibility Complex -genetic locus which determines tissue graft acceptance/rejection -most polymorphic gene in mammals -MHC locus encodes Class 1 and Class II MHC molecules on APCs that display antigen -Class I- CD8+ Cytotoxic T cells -Class II- CD4+ Helper/Regulatory T cells -Both parental alleles of MHC genes are expressed, which increases # MHC molecules that can present peptides to T cells -ALL cells express MHC I (CD8+), Class II (CD4+) MHC is expressed by dendritic cells, macrophages, and B cells -Broad specificity- many different peptides can bind to the same MHC molecule, ,each MHC displays one peptide at a time (can only present peptide antigens)

PRRs

Pattern-recognition receptors -role of PRRs is recognition of infections non self -diverse, many families with distinct and overlapping function -Ligands for PRRs: PAMPs- pathogen-associated molecular patterns, which are structures shared among like pathogens (not self) -Examples of PRRs: Toll Like Receptors -Toll like receptors (example of PRR) initiates signal transduction events that promote immune responses

T cell and B cell Responses to Proteins

T and B cells interact and can be activated by same Ag at same time, then these cells move toward each other in lymph node due to cytokines -if B cells present antigen to T cells that receive this Ag, T cells ramp up B cell response -aggregation of B and T cells is called Germinal Center, where we get isotype switching, affinity maturation, additional memory cells, and long-lived plasma cells (require T cell help) -so we will only get these results if the antigen is a PEPTIDE

Type IV Hypersensitivity Reactions

T-cell Mediated Disease -Primarily caused by autoimmunity and exaggerated responses to enviromental Ags -tissue inflammation/injurt caused by CD4+ derived cytokines or CD8+ killing of host cells -Ex) RA, IBD, Type 1 DM -Delayed-type hypersensitivity (DTH) occurs 1-2 days after previously exposed individual encounters an Ag, PPD test is a DTH reaction

Innate Immunity

always present given cells are equal, diverse repertoire of receptors, respond to many stimuli -fast but less selective -collaborates with adaptive immunity

Capture and Presentation of Antigen

--protein antigens from microbes are captured by dendritic cells and concentrated in peripheral lymphoid tissue -free antigen also travels to the spleen via blood, is captured by APCs there -Lymph nodes attract naive T cells (via chemokines) and T cells interact with APCs

COnsequences of Leukocyte Activation

-Activation of a leukocyte: microbe binds to TLR (PRR) which causes production of more cytokines, cytokine binds to cytokine receptor which causes more cytokines, complement fragment binds to complement receptor which triggers phagocytosis of microbe into phagosome

Type II Hypersensitivity Reactions

-Antibody-mediated injury, antibodies bind to antigen on target cells/tissue to initiate 1) Fc mediated inflammation, classical complement cascade, 2) opsonophagocytosis, both of which lead to tissue injury and 3) binding cell surface receptors to initiate unwanted induction or inhibition of cellular processes (this is "Type V")

Consequences of CD4+T Cell Activation

-CD4 T cells can be subdivided based on how they are activated, depending on cytokines present during activation 1) Th1 CD4 cells stimulate phagocyte-mediated ingestion and killing of microbes, defend against intracellular microbes SIGNIATURE CYTOKINE- IFNgamma 2) Th2 CD4 cells stimulate phagocyte-independent eosinohilic mediated immunity against helminths, inhibit Th1 response, and promote allergy by increasing IgE production (by promoting B cells) and mast cell degranulation- SIGNATURE CYTOKINES OF TH2- IL4, IL5, IL13 3) Th17 CD4 cells induce inflammation and phagocyte recruitment for elimination of bacteria and fungi, defend against extracellular pathogens- SIGNIATURE CYTOKINES are IL17A, IL17F, and IL22 -these promote characteristics of cellular and humoral immunity

T cells after Antigen Recognition

-CD4+ T Helper cells encounter APCs with antigen and then release cytokines that lead to macrophage activation and destruction of phagocytosed antigen. CD4 T Helper cells can recognize antigen presented by B cells, and these T cells then release cytokines to ramp up B cell antibody secretion, antibodies can then neutralize microbes -MHC I-associated presentation of antigen to a CD8+ Cytotoxic T Lymphocyte leads to killing of antigen-expressing target cell -so cellular immunity targets intracellular microbes by CD4 T cells activating phagocytes for microbial killing (and facilitate everything) and by CD8 CTLs inducing apoptotic death of infected self cells

Cytokines

-Diverse, dynamically regulated proteins that enable communication among cells of immune system -Primary functions are grown, differentiation, and/or activation of leukocytes, inflammation -Chemokines are a category of cytokines that direct leukocyte migration (chemotaxis)

Antigen recognition

-In T lymphocytes: T cell receptor (TCR) -In B lymphocytes: Membrane-bound antibodies recognize antigen- the Variable region is the antigen recognition domain which makes each cell unique and antigen receptors are associated with the Constant region that delivers intracellular signals -Lymphocyte antigen receptor diversity is the primary factor driving the diversity of the adaptive immune system-- important!!

Stimulation of Adaptive Immunity

-Innate immune responses include pathogen recognition by PRRs, cytokines are released, promoting more cytokine production or phagocytosis- all of which is innate. -These also can help trigger adaptive immune response ie) one bridge bw innate and adaptive is dendritic cell recognizing and capturing pathogen. Cytokine responses from neutrophils and macrophages (innate) instruct T cells to proceed to activation (adaptive)

NK Cells

-Innate lymphocytes -similar to T cells in morphology, development, and function but do not express antigen-specific T cell receptors -part of innate, not adaptive, immune system -unlike T cells of adaptive immunity ,NK cells each recognize same repertoire of stimuli -NK cell activating receptors recognize infected cells, injured cells, and cells labeled with antibody -NK activation results in cytokine production and/or emptying of cytoplasmc granules which contain cytolytic enzymes

Antibody Isotypes

-Isotype switching requires CD4+ T Helper Cells, elicited by peptide antigen in Germinal Center -B cells undergo isotype switching -Only 4 are secreted: IgG, IgA, IgM, IgE (GAME, IgD is on surface but not secreted) -IgG- does EVERYTHING (neutralization, opsonization, activation of classical pathway of complement, NK cell mediated cytotoxicity, etc), requires help from Th1 -IgA- mucosal immunity, secretion of IgA into GI and resp tracts, neautralization of microbes -IgM- DEFAULT, activation of classical pathway of complement -IgE- defense against helminths, mast cell degranulation, -->allergy, requires help from Th2

Presentation of Antigen to T Cells

-MHC requirement ensures T cell responses only occur to antigen which is associated to an APC, which reduces the change of immune response to harmless substances and brings T cell i proximity of other molecules on/near APC surface required for appropriate activation -The different processing pathways of MHC I and II enable responses to diverse pathogens (intra and extracellular) **B cells do not require MHC for antigen presentation, and B lymphocyte activation can be assisted by unprocessed antigen presentation from other cells, and also can act independently, B cells can also present antigen to T cells

Immune Response to Tumors

-Main mechanisms are CD8 CTL responses to cells with tumor antigen, these cells can get engulfed by dendritic cell, Ag is presented, CD8 CTL response activated and CD8 T cells differentiate, sometimes helped by CD4 T Helper cells

B Lymphocytes

-Mature in the bone marrow -Naive B cells are raised against single pathogens, recognized via unique B cell antibody receptors, 1 B cell, 1 target -can recognize native antigen -Primary function- activated B cells clonally expand and become plasma cells which secrete antibodies that target specific microbes for eradication -B cells can also function as APCs

T Lymphocytes

-Mature in the thymus -Exist in highly diverse subsets distinguished by surface markers called CDs -Naive T cells are raised against single pathogens, recognized via unique T cell receptors, 1 T cell, 1 target ,Ag must be presented via APC -Helper T cells (CD4+) recognize microbial agent presented by APC, clonally expand upon activation and mobilize chemical mediators to promote numerous immunological functions including activating macrophages, inflammation, and activation of T and B lymphocytes -Cytotoxic T cells (CD8+) clonally expand upon activation (recognition of infected cell expressing microbial antigen) and target infected cells for eradication -Regulatory T cells (CD4+) release factors to limit immune response

Barriers to Infection

-Skin, epithelial surfaces, mucus, cilia, hair, coughing and sneezing -longitudinal air flow, tears -Chemical barriers: FAs, acidic environments, enzymes in gut, lysozyme enzymes in tears -Microbiological barrier: Normal flora especially in gut -most vulnerable surfaces are airway, reproductive tract, skin

Innate vs Adaptive Immunity

-Specificity- PRRs (innate) bind to lots of different microbes whereas in adaptive immunity an antibody binds to only one microbe -Receptors- In innate immunity, receptors have limited diversity, are encoded in germline, PRRs. In adaptive immunity, TCRs are encoded by genes produced by somatic recombination so very high diversity. -Distribution- In innate immunity, distribution is non-clonal so identical receptors are on all cells of same linage, whereas in adaptive immunity distribution is clonal so clones of lymphocytes with distinct specificity express different receptors

Dendritic Cells

-Type of antigen presenting cell (macrophages and B cells are other APCs), -serve as bridge between innate and adaptive immunity -long projections (dendrites) are used to contact and engulf foreign material -they are prominent in skin, mucosa, and tissue -Primary function is to travel to lymph nodes following uptake of microbes, and display antigen for lymphocyte activation

Mast Cells

-Type of non-neutrophil granulocytes -Contain cytoplasmic granules filled with histamine -responsible for many symptoms of allergic disease -provide defense against helminths and other microbes (also basophils are similar to mast cells and eosinophils which can damage parasites but also potentially damage host tissue)

Neutrophils

-Type of phagocytes -Also known as PolyMorphoNuclear leukocytes, PMNs -Most abundant circulating leukocyte (60%) which circulates for hours/days and migrates to infected tissues where they are short lived (1-2 days) -Granulocyte- possesses cytoplasmic granules containing enzymes and other antimicrobial substances, primary function is killing via phagocytosis

Macrophages/Monocytes

-Type of phagocytes -Tissue resident macrophages are very long lived sentinel cells -Inflammatory macrophage- circulating monocytes derived from bone marrow migrate to tissues where they mature into inflammatory macrophages -Primary function is killing via phagocytosis, other functions include removal of dead host cells cytokine production, and antigen presentation (APC)

Leukocytes

-White blood cell, cell of immune system

Innate Immune Resposne

-activate and mobilize innate leukocytes, most prominent resident macrophages (long-lived) and neutrophils (recruited, short lived) -more minor role: recruited macrophages, NK cells, dendritic cells

Adaptive Immunity (Acquired)

-adapts to particular invader, given cell recognizes single target while its peers exert same function on different targets, lymphocyte driven, clonal expansion amplifies targeted response -slower but more selective and more robust -collaborates with innate immunity

Complement

-circulating and membrane proteins that assist (complement) antimicrobial activity -activation yields immunologically active complement components via proteolytic cleavage of inactive complement proteins -antibody-dependent complement activation occurs ONLY via classical pathway -other pathways (lectin pathway and alternative pathway) will be considered in innate immunity context

Hypersensitivity Reactions

-excess or aberrant immune responses arising from 1) uncontrolled excessive responses to foreign antigen) or responses to self antigens

Humoral Immunity

-involves macromolecules found in body fluids - typified by antibodies (from B cells) and complement -neutralizes and eliminates extracellular microbes and toxins -this is principal adaptive immune response targeting microbes with capsules containing lipid and polysaccharide, because MHC only present and TCR only recognize peptides

Acute Phase Response

-many different proteins are dumped from liver into circulation, initiated by cytokines (IL-6 is a major innate immunity cytokine) -some cytokines promote or limit inflammation -these are important biomarkers because they are drastically changed in response to infection/injury Ex) Crp- patients with high Crp are more likely to die, high levels of IL-6 indicates higher disease prognosis

B Cell-mediated Immune Response

-naive B cells express TWO forms of antibody as membrane bound surface receptors, IgD and IgM (DM) -engagement of these receptors promote clonal expansion and differentiation into plasma cells -Antibodies on B Cells can bind free Ag, can differentiate and become 1) effector B cells (antibody secreting), 2) IgG expressing B cells (requiring T helper assistance), 3) high affinity IgG expressing B cells (requiring T helper cells), or 4) high affinity Ig expressing memory B cells -responses to Ags are T cell-dependent (proteins) and T cell independent (lipids, sugars) -Activation can lead to class switching and affinity maturation

Inflammation

-recruitment of innate immune cells from the blood into a tissue is inflammation -resident macrophages have PRRs which recognize microbes, release chemokines and cytokines and other inflammatory factors -this causes vasodilation, redness, swelling, heat -inflammatory cells (mostly neutrophils) from circulation migrate into tissue and release inflammatory mediators that cause pain -excessive inflammation can be dangerous

Adaptive Immunity

-requires expansion and differentiation of lymphocytes i response to microbes before it can provide defense -consists of lymphocytes and their products (antibodies) -cellular (cell-mediated) or humoral adaptive immunity -specificity- response is directed toward specific antigens, epitope is the recognized portion of an antigen where lymphocyte binds -diversity- large lymphocyte repertoire allows for wide range of antigenic specificities -memory- Ag exposure enhances response to subsequent exposure via memory T and B cells -clonal expansion- proliferation of lymphocytes following Ag exposure, clones are identical cells specific for many Ags -response contracts and non-memory lymphocytes die of apoptosis after stimulus is gone -self tolerance is enabled by eliminating self-reactive lymphocytes

Evasion of Innate Immunity

-resistance to phagocytosis -resistance to reactive oxygen intermediates in phagocytes -resistance to complement activation (alternative pathway) -resistance to antimicrobial peptide antibiotics

Antibody (Immunoglobulin)

-secreted or membrane bound glycoprotein that binds antigen -IgG, IgA, IgM, IgE, IgD

Consequences of CD8 CTL Activation

-these cells kill infected self cells by inducing apoptosis -CTLs bind to target cells after Ag recognition from MHC I, CTL activates granule exocytosis and these granules contain GRANZYMES (induce apoptosis) and PERFORIN (poke holes, facilitate granzyme entry into cell)

Antibodies

-two identical heavy and light chains with Variable and Constant regions -Fab- domain required for antigen recognition (variable region) -Fc- (constant region) mediates effector functions of Ab by binding Fc receptors to initiate phagocytosis and leukocyte activation and binding complement to activate classical pathway -Antobody effector functions: neutralizing microbes/toxihns, opsonization and phagocytosis of microbes, Abs bind to surgace of infected cell to drive Ab-dependent cellular cytotixcity with NK cells, activation of complement leads to lysis of microbes, phagocytosis of microbes opsonized with complement fragments (such as C3b) and inflammation -Abs can also lead to eosinophil activation and helminth death

Requirements for T Cell Activation

1) Antigen recognition- MHC and TCR interaction 2)Co-stimulation (B7-CD28) 3)Cytokines -will never get T cell activation without all of these -CD8 CTL activation cal also be assisted by CD4+ Thelper Cells- when APC presents Ag to CD8 CTLs, nearby CD4 T helper cells can recognize this Ag and secrete cytokines which encourage clonal expansion and T cell differentiation (paracrine effects)

Primary Effector Mechanisms of Immune System

1) Cytotoxicity- recognizing infected cells to induce apoptosis 2) Phagocytosis- encounters pathogen natively or due to opsonization and engulfs/destroys pathogen 3) Membrane attack complex- formed by complement, causes hole i microbe that kills it 4) Neutralization- antibodies bind to a pathogen to neutralize it

Primary Activation of Leukocytes

1) Direct stimulation by PRRs 2) Indirect stimulation by opsonin receptors (Fc/complement receptors), Fc receptor on macrophage recognizes Fc protion of Ab on pathogen 3) Cytokines- 3a) multifactorial/early response cytokines (EXAMPLES: TNF, IL-1, IL-6**) which activate cells and promote inflammation and 3b) Chemokines (EXAMPLE CXCL8) which promote chemotaxis

Leukocyte Distribution

1) Generative (Primary) Lymphoid organs- Bone Marrow is site of all progenitors for leukocytes and site of B cell maturation. Thymus is site of T cell maturation. 2) Peripheral (secondary) lymphoid organs- Promote immune interactions, retain naive cells, mobilize active cells. Lymph nodes are aggregates of tissue along lymphatic channels, are exposed to lymph draining from blood and tissues, concentrate antigens, APCs, and lymphocytes for immune activation. The spleen is highly vascularized and serves a similar purpose as lymph nodes for blood borne agents. Mucosal and cutaneous lymphoid tissue are additional concentrated areas of immune activity such as tonsils, Peyer's patches, and respiratory tract.

Mechanisms of Pathogen Eradication in Innate Immunity

1) Phagocytosis- especially by neutrophils and macrophages, microbes are recognized by receptors (PRRs, opsonin receptors, or complement receptors), microbe is ingested and exposed to lysosomes with digestive enzymes bia phagolysosome formation inside the phagocyte, microbe is exposed to enzymes which produce NO and ROS to kill microbe -Chronic Granulomatous DIsease is severe immunodeficiency due to lack of phagocyte oxidase (which produces NO and ROS to kill microbes) 2)Innate antiviral defense- largely mediated by interferons, cytokine that interferes with virus replication by inhibiting protein synthesis inside virally infected cell, degrading viral RNA, inhibiting viral gene expression 3) NK cells- innate lymphocytes which have receptors that recognize and kill infected cells (similar to CD8 CTLs), and produce cytokines to activate macrophage defense 4) Complement- complement cascade can be initiated directly or indirectly -classical pathway is AB-mediated, C1 binds to antibody complonent to form Crb -alternative pathway to complement activation is when C3b binds directly to microbe (does not need Ab) -lectin pathway is when a molecule in body (mannose binding lectin) pretends to be C1 and binds mannose, kicking of complement cascade (again without Ab)

Antigen (Ag)

molecule (typically foreign) recognized by some WBCs

Lymphocytes

Backbone of adaptive immunity, launch distinct and robust responses to specific simple target (single antigen) Ex) B-lymphocytes, T-lymphocytes however, there are innate lymphocytes which are functionally and morphologically similar to adaptive lymphocytes but are not Ag-specific Ex) Natural Killer NK Cells -30% of WBC