Robbins and Cotran Chapter 6

What defines pathologic autoimmunity

(1) the presence of an immune reaction specific for some self antigen or self tissue; (2) evidence that such a reaction is not secondary to tissue damage but is of primary pathogenic significance; and (3) the absence of another well-defined cause of the disease.

What causes amylodosis

-Extracellular deposits of fibrillar protein -> tissue damage and funcitonal compromise -Aggregations of misfolded proteins that bind proteoglycans and gycosaminoglycans and plasma protein. -Stains like starch (amylose) d/t abundant charged sugar groups, though amyloid is unreladed to starch -Deposited in extracellular space -> pressure atrophy. Congo red positive. -all amyloid consists of continuous, nonbranching fibrils 7.5-10 nm with characteristic cross-β-pleated sheet conformation (causes bifringence)

Important NK cell pacts

-Recognize and destroy severely stressed/abnormal cells (virus-infected or tumor) -Express CD16- receptor for IgG Fc tails so NK cells can lyse IgG-coated cells (antibody-dependent cellular toxicity) -NK cell inhibitory receptors recognize self class I MHC molecules on all healthy cells. Sick cells often downregulate MHC I expression -NK cells secrete cytokines like IFN-γ (activates macrophages to ingest microbes) -Proliferation of NK cells is stimulated by IL2 and IL15 -Activity of NK cells is regulated by IL2, IL15, IL12, and others. IL12 activates killing of target cells and secretion of IFN-gamma

Important allograft recognition and rejection facts

-Rejection from different HLA alleles (highly polymophic). Recepient T cells recognize donor HLA antigens from eitherdirect presentation of graft antigen by graft APCs to recipient Tcells OR the graft antigens are picked up by host APC, processed, and presented to host Tcells. Both lead to activation of CD8+ t CELLS AND cd4+ cellls (mainly TH1). Direct pathway= acute rejection, indirect=chronic

Describe mechanisms of T cell anergy

-Self-recognizing T cells receive inhibitory singals homologous to CD28 which are CTLA-4 (binds B7) and PD-1 (binds PD-L1 and PD-L2). Some tumors express CTLA-4 and PD-1 to put breaks on immune response. Anergy also affects mature B cells in peripheral tissues. It is believed that if B cells encounter self antigen in peripheral tissues, especially in the absence of specific helper T cells, the B cells become unable to respond to subsequent antigenic stimulation and may be excluded from lymphoid follicles, resulting in their death

Describe primary vs secondary lymphoid organs

1e- The principal primary lymphoid organs are the thymus, where T cells develop, and the bone marrow, the site of production of all other blood cells, including naïve B cells. 2e- The secondary lymphoid organs—lymph nodes, spleen, and the mucosal and cutaneous lymphoid tissues—are the tissues where adaptive immune responses occur . Several features of these organs promote the generation of adaptive immunity—antigens are concentrated in these organs, naïve lymphocytes circulate through them searching for the antigens, and different lymphocyte populations (such as T and B cells) are brought together when they need to interact. Lymph nodes are the site of generation of the majority of adaptive immune responses.

What is a follicular dendritic cell

A second type of cell with dendritic morphology is present in the germinal centers of lymphoid follicles in the spleen and lymph nodes and is called the follicular dendritic cell (FDC) . These cells bear Fc receptors for IgG and receptors for C3b and can trap antigen bound to antibodies or complement proteins. They play a role in humoral immune responses by presenting antigens to B cells in the germinal center, part of a process through which only B cells that express antibodies with high affinity for antigen survive and go on to mature into plasma cells or memory cells.

What does the γδ TCR do

A small population of mature T cells expresses another type of TCR composed of γ and δ polypeptide chains. The γδ TCR recognizes peptides, lipids, and small molecules, without a requirement for display by MHC proteins. γδ T cells tend to aggregate at epithelial surfaces, such as the skin and mucosa of the gastrointestinal and urogenital tracts, suggesting that these cells are sentinels that protect against microbes that try to enter through epithelia. However, the functions of γδ T cells are not established. Another small subset of T cells expresses markers that are also found on NK cells; these cells are called NK-T cells. NK-T cells express a very limited diversity of TCRs, and they recognize glycolipids that are displayed by the MHC-like molecule CD1. The functions of NK-T cells are also not well defined.

What can antinuclear antibodies be directed against

ANAs can be grouped into four categories based on their specificity for: (1) DNA, (2) histones, (3) nonhistone proteins bound to RNA, and (4) nucleolar antigens. Antiphospholipid antibodies are present in 30% to 40% of lupus patients.

What do activated Th17 cells secrete

Activated Th17 cells secrete IL-17, IL-22, chemokines, and several other cytokines. Collectively, these cytokines recruit neutrophils and monocytes to the reaction, thus promoting inflammation.

What is hyper-IgM syndrome?

Affected patients have IgM antibodies but are deficient in IgG, IgA, and IgE antibodies . Mature B cells are incapable of Ig class switching and affinity maturation due to defect in CD4+ Thelpers or intrinsic Bcell defect. CD40 + CD40L triggers class switching and affinity maturation and stimulates microbicidal functions of macrophages. Typically caused by mutation in gene encoging CD40L with autosomal recessive pattern. Can also have loss-of-function mutation involving CD40 or AID (DNA editing) The serum of persons with this syndrome contains normal or elevated levels of IgM but no IgA or IgE and extremely low levels of IgG. The numbers of B and T cells in the blood are normal. Clinically, patients present with recurrent pyogenic infections, because the level of opsonizing IgG antibodies is low, and also because affinity maturation, a process necessary for production of high-affinity antibodies, is impaired. Susceptible to intracellular organisms because macrophage activation is inhibited

Type 1 hypersensitivity reaction facts

Aka immediate hypersensitivity.Rapid rxn in previously-sensitized indvidual trigged by binding of antigen to IgE on surface of mast cells (aka allegies). Two phases- immediate phase has vasodilation, vascular leakage, smooth muscle spasm, gladular secretions. Late phase- infiltration of tissues with eos, neuts, basos, monos, CD4+ T cellls, tissue damage (especially mucosal epithelial cell damage). Most immediate hypersensitivity disorders are caused by excessive Th2 responses, and these cells play a central role by stimulating IgE production and promoting inflammation. TH2 cell activation: CD4+ naive helper T -> antigen presented + IL-4 -> differentiation into Th2 -> Th2 make Il-4/5/13 and chemokines that recruit more Th2 cells and other leukocytes to rxn site. Before Th2 responses develop, type 2 ILCs in tissues may respond to cytokines produced by damaged epithelia. These ILCs secrete IL-5 and IL-13 and are thus able to induce the same tissue reactions as the classical Th2 cells.

What are the different patterns of amyloid accumulation?

Amyloid may be systemic (generalized), involving several organ systems, or it may be localized to a single organ, such as the heart. On clinical grounds, the systemic, or generalized, pattern is subclassified into primary amyloidosis, when it is associated with clonal plasma cell proliferations, or secondary amyloidosis, when it occurs as a complication of an underlying chronic inflammatory process. Hereditary or familial amyloidosis constitutes a separate, albeit heterogeneous, group, with several distinctive patterns of organ involvement.

What is sago spleen

Amyloidosis of the spleen may be inapparent grossly or may cause moderate to marked splenomegaly (up to 800 g). For completely mysterious reasons, one of two patterns of deposition is seen. In one, the deposits are largely limited to the splenic follicles, producing tapioca-like granules on gross inspection, designated sago spleen. In the other pattern, the amyloid involves the walls of the splenic sinuses and connective tissue framework in the red pulp. Fusion of the early deposits gives rise to large, maplike areas of amyloidosis, creating what has been designated lardaceous spleen. Btw, amyloid first apppears in the space of disse in the liver before it encroaches on hepatic parenchyma and sinusoids

What is epitope spreading

An immune response against one self antigen causes tissue damage, releasing other antigens, and resulting in the activation of lymphocytes that recognize these newly encountered epitopes.

Important systemic lupus erythematosus facts (SLE)

Anitnuclear antibodies -> deposition of immune complexes and binding of antibodies to cells. Antibodies to dsDNA (from alleles on HLA-DQ locus) and Sm (smith; same allele; same allele can also cause anti-phospholipid antibodies) antigen are virtually diagnostic.

What false results can lupus patients have

Antibodies against the phospholipid-β 2 -glycoprotein complex also bind to cardiolipin antigen, used in syphilis serology, and therefore lupus patients may have a false-positive test result for syphilis . Some of these antibodies interfere with in vitro clotting tests, such as partial thromboplastin time. Therefore, these antibodies are sometimes referred to as lupus anticoagulant . Despite the observed clotting delays in vitro, however, patients with antiphospholipid antibodies have complications related to excessive clotting (a hypercoagulable state), such as thrombosis

Type 2 hypersensitivity important facts

Antibody + antigen -> cell destruction w/inflammation and loss of function. Cells opsonized by IgG are recognized by phagocyte Fc ane eaten. Deposition of IgM or IgG can activate classical complement pathway and generate C3 cleavage products C3b and C4b -> deposited on cell surface -> phagocytosis and MAC formation -> cell lysis and destruction Antibody-mediated destruction of cells also may occur by another process called antibody-dependent cellular cytotoxicity (ADCC). Cells that are coated with IgG antibody are killed by effector cells, mainly NK cells and macrophages, which bind to the target by their receptors for the Fc fragment of IgG, and cell lysis proceeds without phagocytosis. The contribution of ADCC to common hypersensitivity diseases is uncertain. Inflammation caused by antibodies binding to basement membranes/extracellular matrix and activating complement, generating C5a (chemotactic and anaphylotoxin) and C3a (anaphlotoxin) The leukocytes are activated by engagement of their C3b and Fc receptors. This results in the release of substances from the leukocytes that damage tissues, such as lysosomal enzymes, including proteases capable of digesting basement membrane, collagen, elastin, and cartilage, and by generation of reactive oxygen species.

What generates antigen receptor diversity

Antigen receptor diversity is generated by somatic recombination of the genes that encode antigen receptors. All cells of the body, including lymphocyte progenitors, contain antigen receptor genes in the germline (inherited) configuration, in which the genes encoding these receptors consist of spatially separated segments that cannot be expressed as mRNAs. During lymphocyte maturation (in the thymus for T cells and the bone marrow for B cells), these gene segments are assembled by recombination, and DNA sequence variation is introduced at the sites where the gene segments are joined. This creates many different genes that can be transcribed and translated into antigen receptors with diverse amino acid sequences, particularly in the regions of the receptors that recognize and bind antigen. The enzyme in developing lymphocytes that mediates recombination of these gene segments is the product of RAG-1 and RAG-2 (recombination-activating genes); inherited defects in RAG proteins result in a failure to generate mature lymphocytes. -The TCR in T cells and Ig in B cells are the recombined antigen receptor genes and are markers of T or B cell lineage

Name examples of Type II hypersensitivity

Autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, phemphigus vulgaris, Goodpasture syndrome (noncollagenous protein in basement membranes of kidney glomeruli and lung alveoli), myasthenia gravis

Autosomal recessive SCID

Autosomal recessive. Most commone one is deficiency in adenosine deaminase (ADA) -> accumulation of deoxyadenosine and derivatives thereof -> toxic to rapidly dividing immature lymphs, especially Tcells Can also have following mutations: RAG (cannot perform somatic gene rearrangment for TCR/IG assembly so T and Bcells don't develop), JAK3 (same effect as mutations in yc chain), others. In yc mutation and ADA deficiency the thymus is small and devoid of lymphoid cells

If Bcells detect what antibody they will shut off further antibody production?

B cells express an Fc receptor that recognizes IgG antibodies bound to antigens and switches off further antibody production (a normal negative-feedback mechanism). Knockout of this receptor results in autoimmunity, presumably because the B cells can no longer be controlled.

For type 4 hypersensitivities, what is the difference between Th1 and Th17 mediated responses

Both Th1 and Th17 cells contribute to organ-specific diseases in which inflammation is a prominent aspect of the pathology. The inflammatory reaction associated with Th1 cells is dominated by activated macrophages, and that triggered by Th17 cells has a greater neutrophil component.

Name cellular recptors involved in detecting microbial products

C-type lectin receptors (CLRs) expressed on the plasma membrane of macrophages and DCs detect fungal glycans and elicit inflammatory reactions to fungi. RIG-like receptors (RLRs), named after the founding member RIG-I (retinoic acid-inducible gene-I), are located in the cytosol of most cell types and detect nucleic acids of viruses that replicate in the cytoplasm of infected cells. These receptors stimulate the production of antiviral cytokines. Cytosolic receptors for microbial DNA, often derived from viruses in the cell, activate a pathway called STING (for stimulator of interferon genes), which leads to the production of the antiviral cytokine interferon-α. Excessive activation of the STING pathway causes systemic inflammatory disorders collectively called interferonopathies . Plasma membrane G protein-coupled receptors on neutrophils, macrophages, and most other types of leukocytes recognize short bacterial peptides containing N -formylmethionyl residues. Because all bacterial proteins and few mammalian proteins (only those synthesized within mitochondria) are initiated by N -formylmethionine, this receptor enables neutrophils to detect bacterial proteins and move toward their source (chemotaxis). Mannose receptors recognize microbial sugars (which often contain terminal mannose residues, unlike mammalian glycoproteins) and induce phagocytosis of the microbes.

What do different deficiencies in complement cause

C2 or C4- early components of classical pathway; may have increased infections or no manifestation if alternative pathway takes over Alt. pathway def- properdin and factor D, rare, recurrent pyogenic infections C3- needed for both pathways; serious recurrent pyogenic infections with increased immune complex-mediated glomerulonephritis Terminal components- C5-9 so no MAC so increased susceptibility to recurrent Neisseria infections (thin cell wall makes them susceptible to lytic action) Defective mannose binding lectin = increased infections A deficiency of C1 inhibitor (C1 INH) gives rise to hereditary angioedema. The C1 inhibitor's targets are proteases, specifically C1r and C1s of the complement cascade, factor XII of the coagulation pathway, and the kallikrein system. With deficiency of C1 INH, unregulated activation of kallikrein may lead to increased production of vasoactive peptides such as bradykinin.

What do CD4+ vs CD8+ t cells do

CD4 and CD8 are expressed on two mutually exclusive subsets of αβ T cells. Normally, approximately 60% of mature T cells are CD4+, and about 30% are CD8+. Most CD4+ T cells function as cytokine-secreting helper cells that assist macrophages and B lymphocytes to combat infections. Most CD8+ cells function as CTLs that destroy host cells harboring microbes. CD4 and CD8 serve as coreceptors in T-cell activation. During antigen recognition, CD4 molecules bind to class II MHC molecules that are displaying antigen (see Fig. 6.6 ); CD8 molecules bind to class I MHC molecules; and the CD4 or CD8 coreceptor initiates signals that are necessary for activation of the T cells. Because of this requirement for coreceptors, CD4+ helper T cells can recognize and respond to antigen displayed only by class II MHC molecules, whereas CD8+ cytotoxic T cells recognize cell-bound antigens only in association with class I MHC molecules

What cell type mediates type 1 diabetes

CD8+ CTLs Also play important role in graft rejection, destroying virus infected cells expressing viral peptides on MHC class 1, or killing of cells if expressing tumor antigen

What is primary amyloidosis

Caused by a clonal proliferation of plasma cells that synthesize an Ig light chain that is prone to form amyloid due to its intrinsic physiochemical properties. he malignant plasma cells synthesize abnormal amounts of a single Ig, producing an M (myeloma) protein "spike" on serum electrophoresis. In addition to the synthesis of whole Ig molecules, the malignant plasma cells often secrete free, unpaired κ or λ light chains (referred to as Bence-Jones protein). These are often found in the serum, and due to their small molecular size, Bence-Jones proteins are excreted and concentrated in the urine. In primary amyloidosis, the free light chains are not only present in serum and urine but are also deposited in tissues as amyloid. It should be noted, however, that the majority of myeloma patients who have free light chains in serum and urine do not develop amyloidosis. Most persons with AL amyloid do not have classic multiple myeloma or any other overt B-cell neoplasm; such cases have been traditionally classified as primary amyloidosis, because their clinical features derive from the effects of amyloid deposition without any other associated disease.

X- linked lymphoproliferative disease

Characterized by an inability to eliminate EBV, eventually leading to fulminant infectious mononucleosis and the development of B-cell tumors. In about 80% of cases, the disease is due to mutations in the gene encoding an adapter molecule called SLAM-associated protein (SAP). SAP binds to a family of cell surface molecules involved in the activation of NK cells and T and B lymphocytes, including the signaling lymphocyte activation molecule (SLAM). Defects in SAP attenuate NK and T-cell activation and result in increased susceptibility to viral infections. SAP is also required for the development of T follicular helper cells, and because of this defect X-linked lymphoproliferative disease patients are unable to form germinal centers or produce high-affinity antibodies, additional abnormalities that also likely contribute to susceptibility to viral infection. This immunodeficiency is most commonly manifested by severe EBV infection, including severe and often fatal infectious mononucleosis ( Chapter 8 ), but not other viral infections, for reasons that are not clear.

What are the subtypes of lupus

Chronic discoid lupus erythematosis- usually limited to just skin; characterized by the presence of skin plaques showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy surrounded by an elevated erythematous border; deposition of immunoglobulin and C3 at the dermoepidermal junction Subacute cutaneous lupus erythematosis- features intermediate between SLE and chronic discoid LE SLE-like syndrome can be drug-induced

Important MHC II facts

Class II MHC molecule s are encoded in a region called HLA-D, which has three subregions: HLA-DP, HLA-DQ, and HLA-DR . Each class II molecule is a heterodimer consisting of a noncovalently associated α chain and β chain, both of which are polymorphic. The extracellular portions of the α and β chains both have two domains designated α 1 and α 2 , and β 1 and β 2 . The crystal structure of class II molecules has revealed that, similar to class I molecules, they have peptide-binding clefts facing outward (see Fig. 6.9 ). This cleft is formed by an interaction of the α 1 and β 1 domains, and it is in this portion that most class II alleles differ. Thus, as with class I molecules, polymorphism of class II molecules is associated with differential binding of antigenic peptides. Class II MHC molecules present antigens derived from extracellular microbes and proteins following their internalization into endosomes or lysosomes. Here, the internalized proteins are proteolytically digested, producing peptides that then associate with class II heterodimers in the vesicles, from which they are transported to the cell surface as stable peptide-MHC complexes. The class II β 2 domain has a binding site for CD4, and therefore, the class II-peptide complex is recognized by CD4+ T cells, which function as helper cells. Because CD4+ T cells can recognize antigens only in the context of self class II molecules, they are referred to as class II MHC-restricted. In contrast to class I molecules, class II molecules are mainly expressed on cells that present ingested antigens and respond to T-cell help (macrophages, B lymphocytes, and DCs)

What to IFN-gamma-activated macrophages do

Classically-activated macrophages; their ability to phagocytose and kill microorganisms is markedly augmented; they express more class II MHC molecules on the surface, enhancing antigen presentation; they secrete TNF, IL-1, and chemokines, which promote inflammation ( Chapter 3 ); and they produce more IL-12, amplifying the Th1 response.

What happens in urushiol reactions

Contact dermatitis (vesicular, itchy). Chemical binds to and structuarlly modifies self protein and peptides derived from these modified proteins are recognized by T cell and elicit rxn. Chemical can also modify HLA so they look foreing to T cells (mechanism responsible for most drug rxns) CD4+ T cell-mediated inflammation is the basis of tissue injury in many organ-specific and systemic autoimmune diseases

What do dendritic cells do in the innate immue system

Dendritic cells (DCs) are specialized cells present in epithelia, lymphoid organs, and most tissues. They capture protein antigens and display peptides for recognition by T lymphocytes. In addition to their antigen-presenting function, DCs are endowed with a rich collection of receptors that sense microbes and cell damage and stimulate the secretion of cytokines, mediators that play critical roles in inflammation and antiviral defense. Thus, DCs serve as sentinels that detect danger and initiate innate immune responses, but, unlike macrophages, they are not key participants in the destruction of microbes and other offending agents.

DiGeorge Syndrome (Thymic Hypoplasia)

DiGeorge syndrome is a T-cell deficiency that results from failure of development of the thymus . The third and fourth pharyngeal pouches, which give rise to the thymus, the parathyroids, some of the C cells of the thyroid, and the ultimobranchial body, do not develop normally. Absence of cell-mediated immunity is caused by low numbers of T lymphocytes in the blood and lymphoid tissues and poor defense against certain fungal and viral infections. The T-cell zones of lymphoid organs—paracortical areas of the lymph nodes and the periarteriolar sheaths of the spleen—are depleted. Ig levels may be normal or reduced, depending on the severity of the T-cell deficiency. caused by a small germline deletion that maps to chromosome 22q11

What is isotype switching? Affinity maturation?

Each plasma cell is derived from an antigen-stimulated B cell and secretes antibodies that recognize the same antigen that was bound by the BCR to initiate the response. Polysaccharides and lipids stimulate secretion mainly of IgM antibody. Protein antigens, by virtue of CD40L- and cytokine-mediated helper T-cell actions, induce the production of antibodies of different classes, or isotypes (IgG, IgA, IgE), a process called isotype switching . Helper T cells also stimulate the production of antibodies with high affinities for the antigen. This process, called affinity maturation, improves the quality of the humoral immune response. These two processes are initiated when activated B cells that receive signals from helper T cells during responses to protein antigens migrate into follicles and begin to proliferate to form germinal centers, which are the major sites of isotype switching and affinity maturation. The helper T-cells that stimulate these processes in B lymphocytes also migrate to and reside in the germinal centers and are called T follicular helper (T fh ) cells.

What can lupus patients lack?

Early complement components (C2/4/1q). Can impair removal of circulating immune complexes and loss of B-cell otlerance. Deficiency of C1q -> defective phagocytic clearance of apoptotic cells

How does epithelium play a role in the innate immune system

Epithelia of the skin and gastrointestinal and respiratory tracts act as mechanical barriers to the entry of microbes from the external environment. Epithelial cells also produce antimicrobial molecules such as defensins, and lymphocytes located in the epithelia combat microbes at these sites. If microbes breach epithelial boundaries, other defense mechanisms come into play.

Environmental factors that affect lupus

Exposure to UV light induces apoptosis and can alter DNA so its TLR recoginition is enhanced. UV light can also stimulate keratinocytes to produce Il-1 (promotes inflammation)

What causes T cells to apoptose when they recognize self

Expression of Bim (Bcl family member) unopposed by anti-apoptotic BCL-2 and BCL-x trigges apoptosis via mitochondrial pathway Can use Fas-Fas ligand system where self-reactive lymphocytes express Fas (CD95) and binds with FasL on activated T lymphocytes. If self antigens engage antigen receptors of self-reactive T cells, Fas and FasL are co-expressed, leading to elimination of the cells via Fas-mediated apoptosis. Self-reactive B cells may also be deleted by FasL on T cells engaging Fas on the B cells. Mutation in Fas/FasL -> autoimmune lymphoproliferative syndrome

What three molecules do Tregs need to function What do Tregs secrete

FOXP3, IL-2 alpha chain, and CD25 IL-10 and TGF-beta (inhibit lymphocyte activatioin and effector functions)

This is not a part of this chapter, but this image needed to go somewhere.... Describe the ECM, endothelial, and leukocyte molecules involved in leukocyte paracellular transmigration (diapedesis)

Figure 1. Sequential steps in leukocyte emigration are controlled by interactions between specific molecules on leukocytes and their counterreceptors on endothelial cells. The steps in leukocyte emigration described in the text are depicted schematically here. For each step, the molecules that interact between leukocyte and endothelial cell are printed in the same color. This diagram is not all-inclusive, and other molecules may mediate each of these events for distinct leukocyte types under different inflammatory conditions. Endothelial cells are depicted in blue and the leukocytes in pink with blue nuclei. Protrusions on the leukocyte surface in the capture/tethering step represent microvilli that bear Lselectin and very late antigen 4 (VLA-4). The lightning bolt at the activation step represents the triggering of inside-out activation of leukocyte integrins by signals from the endothelium and endothelial surface via G protein-coupled receptors. Parentheses around LFA-1 and ICAM-2 in the locomotion step indicate that these molecules have been shown to play a role in this step for monocytes in vitro but have not been verified in vivo. The basal lamina is depicted as the orange strip separating the underside of the endothelium from the remainder of the extracellular matrix (ECM). Many members of the b1 family of integrins are involved in migration through the ECM and are represented by ''b1.'' Most of the b1 ligands are not listed on the ECM side of this cartoon. ESL-1, E-selectin ligand 1; s-Lex sialyl-Lewis x antigen; VCAM-1, vascular cell adhesion molecule 1; PSGL-1, P-selectin glycoprotein ligand 1; LFA-1, lymphocyte function-associated antigen 1; Mac-1, macrophage-1 antigen; PAF, platelet activating factor; PAF-R, PAF receptor; ICAM, intercellular adhesion molecule; PECAM-1, platelet/endothelial cell adhesion molecule 1; PECAM-1 (d1/2), PECAM-1 domains 1 and 2 are responsible for this step; PECAM-1 (d6), PECAM-1 domain 6 is responsible for this step; a6b1, VLA-6, the integrin responsible for binding laminin; HSPG, heparan sulfate proteoglycan.

Subsets of helper T cells and what they do

Figure 6.11 Subsets of helper T (Th) cells. In response to stimuli (mainly cytokines) present at the time of antigen recognition, naïve CD4+ T cells may differentiate into populations of effector cells that produce distinct sets of cytokines and perform different functions. The dominant immune reactions elicited by each subset, and its role in host defense and immunologic diseases, are summarized. These populations may be capable of converting from one to another. Some activated T cells produce multiple cytokines and do not fall into a distinct subset.

Schematic of humeral immunity

Figure 6.12 Humoral immunity. Naïve B lymphocytes recognize antigens, and under the influence of helper T cells and other stimuli (not shown), the B cells are activated to proliferate and to differentiate into antibody-secreting plasma cells. Some of the activated B cells undergo heavy-chain class switching and affinity maturation, and some become long-lived memory cells. Antibodies of different heavy-chain classes (isotypes) perform different effector functions, shown on the right. Note that the antibodies shown are IgG; these and IgM activate complement; and the specialized functions of IgA (mucosal immunity) and IgE (mast cell and eosinophil activation) are not shown.

What is within the granules of mat cells

Granule contents. Mediators contained within mast cell granules are the first to be released and can be divided into three categories: • Vasoactive amines . The most important mast cell-derived amine is histamine ( Chapter 3 ). Histamine causes intense smooth muscle contraction, increases vascular permeability, and stimulates mucus secretion by nasal, bronchial, and gastric glands. • Enzymes. These are contained in the granule matrix and include neutral proteases (chymase, tryptase) and several acid hydrolases. The enzymes cause tissue damage and lead to the generation of kinins and activated components of complement (e.g., C3a) by acting on their precursor proteins. • Proteoglycans. These include heparin, a well-known anticoagulant, and chondroitin sulfate. The proteoglycans serve to package and store the amines in the granules. Lipid mediators.The major lipid mediators are arachidonic acid-derived products (Chapter 3). Mast cell activation is associated with activation of phospholipase A2, an enzyme that converts membrane phospholipids to arachidonic acid. This is the parent compound from which leukotrienes and prostaglandins are produced by the 5-lipoxygenase and the cyclooxygenase pathways, respectively. • Leukotrienes. Leukotrienes C 4 and D 4 are the most potent vasoactive and spasmogenic agents known. On a molar basis, they are several thousand times more active than histamine in increasing vascular permeability and causing bronchial smooth muscle contraction. Leukotriene B 4 is highly chemotactic for neutrophils, eosinophils, and monocytes. • Prostaglandin D 2 . This is the most abundant mediator produced in mast cells by the cyclooxygenase pathway. It causes intense bronchospasm and increases mucus secretion. • Platelet-activating factor (PAF). PAF ( Chapter 3 ) is a lipid mediator produced by some mast cell populations that is not derived from arachidonic acid. It causes platelet aggregation, histamine release, bronchospasm, increased vascular permeability, and vasodilation. Its role in immediate hypersensitivity reactions is not well established.

What is the role of type 1 interferons in lupus (SLE)?

High levels of type 1 inteferons correlate with disease severity. They are antiviral cytokines normally produced during innate immune responses to viruses. It may be that nucleic acids engage TLRs on DCs and stimulate the production of interferons. In other words, self nucleic acids mimic their microbial counterparts.

What are the different classifications of graft rejection

Hyperactute- mediated by preformed antibodies specific for antigens on graft endothelial cells (may be natural IgM against blood grops or specific for allogenic MHC from prior exposure through transfusion, pregnancy, or organ transplantation. Ab + graft vascular endothelium -> complement activation -> endothelial injury, thrombosis, graft ischemia necrosis Acute- mediated by Tcells and antibodies activated by alloantigens in graft days to weeks after transplantation or much later if immunosuppression removed. Based on the role of T cells or antibodies, acute rejection is divided into two types, although in most rejecting grafts, both patterns are present. In acute cellular rejection, CD8+ CTLs may directly destroy graft cells, or CD4+ cells secrete cytokines and induce inflammation, which damages the graft. T cells may also react against graft vessels, leading to vascular damage. Current immunosuppressive therapy is designed mainly to prevent and reduce acute rejection by blocking the activation of alloreactive T cells. In acute antibody-mediated (vascular, or humoral) rejection, antibodies bind to vascular endothelium and activate complement via the classical pathway, resulting in graft failure Chronic rejection- takes months or year. See interstitial fibrosis and narrowing of graft vessels aka graft arteriosclerosis.In both lesions, the culprits are believed to be T cells that react against graft alloantigens and secrete cytokines, which stimulate the proliferation and activities of fibroblasts and vascular smooth muscle cells in the graft. Alloantibodies also contribute to chronic rejection

What do dendritic cells drive the production of when they produce... -Il-12 IFN-gamma -Il-1 -Il-6 -Il-23

IL-1/6/23 -> Th17 Il-12-> CD4+ cells become Th1 IFN-gamma production promotes further Th1 development

What do each of the different antibody types do

IgG antibodies coat (opsonize) microbes and target them for phagocytosis, since phagocytes (neutrophils and macrophages) express receptors for the Fc tails of IgG. IgG and IgM activate the complement system by the classical pathway, and complement products promote phagocytosis and destruction of microbes. Some antibodies serve special roles at particular anatomic sites. IgA is secreted from mucosal epithelia and neutralizes microbes in the lumens of the respiratory and gastrointestinal tracts (and other mucosal tissues). IgG is actively transported across the placenta and protects the newborn until the immune system becomes mature. IgE and eosinophils cooperate to kill parasites, mainly by release of eosinophil granule contents that are toxic to the worms. As mentioned earlier, Th2 cytokines stimulate the production of IgE and activate eosinophils, and thus the response to helminths is orchestrated by Th2 cells. Most circulating IgG antibodies have half-lives of about 3 weeks.

What are IgG4-related disease

IgG4-related disease (IgG4-RD) is a constellation of disorders characterized by tissue infiltrates dominated by IgG4 antibody-producing plasma cells and lymphocytes (particularly T cells), fibrosis, obliterative phlebitis, and usually increased serum IgG4 .

How does central tolerance develop

Immature self-reactive T and B lymphocyte clones that recognize self antigens during their maturation in the central (primary, or generative) lymphoid organs (the thymus for T cells and the bone marrow for B cells) are killed or rendered harmless. When immature T cells expressing TCRs specific for self antigens encounter these antigens in the thymus, signals are produced that result in killing of the cells by apoptosis. This process is called negative selection or clonal deletion. Autoologous protein antigens are processed and presneted by thymic APCs in association with self MHC so self-reactive Tcells can recognize it and be eliminated

Type III hypersensitivity important facts

Immune-complex mediated; Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition. Complexes deposit in vessel walls or, less frequently, where antigen was planted previously. Disease tends to be systemic but preferentially involve kidney, joints, and small blood vessels

What cytokines are involved in the adaptive immune response

In adaptive immune responses, cytokines are produced principally by CD4+ T lymphocytes activated by antigen and other signals, and they function to promote lymphocyte proliferation and differentiation and to activate effector cells. The main ones in this group are IL-2, IL-4, IL-5, IL-17, and IFN-γ; their roles in immune responses are described later. Some cytokines serve mainly to limit and terminate immune responses; these include TGF-β and IL-10.

What is MHC (aka HLA)

In humans, the MHC molecules are called human leukocyte antigens (HLA) because they were initially detected on leukocytes. The genes encoding HLA molecules are clustered on a small segment of chromosome 6 ( Fig. 6.9 ). The HLA system is highly polymorphic; there are thousands of distinct MHC gene alleles in humans, and as a result each individual's HLA alleles differ from those inherited by most other individuals in the population. This, as we see subsequently, constitutes a formidable barrier in organ transplantation.

What cytokines are involved in the innate imune response

In innate immune responses, cytokines are produced rapidly after encounter with microbes and other stimuli, and they function to induce inflammation and inhibit virus replication. These cytokines include TNF, IL-1, IL-12, type I IFNs, IFN-γ, and chemokines ( Chapter 3 ). Their major sources are macrophages, DCs, ILCs, and NK cells, but endothelial and epithelial cells can also produce them.

How are B and T cells arranged in lymph nodes and spleen

In lymph nodes, the B cells are concentrated in discrete structures, called follicles, located around the periphery, or cortex, of each node. If the B cells in a follicle have recently responded to an antigen, this follicle may contain a central region called a germinal center. The T lymphocytes are concentrated in the paracortex, adjacent to the follicles. The follicles contain the FDCs that are involved in the activation of B cells, and the paracortex contains the DCs that present antigens to T lymphocytes. In the spleen, T lymphocytes are concentrated in periarteriolar lymphoid sheaths surrounding small arterioles, and B cells reside in follicles akin to those found in lymph nodes (the so-called splenic white pulp).

How does Type 2 hypersensitivity cause cellular dysfunction

In some cases, antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation (see Fig. 6.16C ). For example, in myasthenia gravis, antibodies reactive with acetylcholine receptors in the motor end plates of skeletal muscles block neuromuscular transmission and therefore cause muscle weakness. The converse (i.e., antibody-mediated stimulation of cell function) is the basis of Graves disease. In this disorder, antibodies against the thyroid-stimulating hormone receptor on thyroid epithelial cells stimulate the cells, resulting in hyperthyroidism.

In what way are antibody responses T- dependent? What types of molecules may trigger a T-independent response?

In these responses, B cells that recognize protein antigens by their Ig receptors endocytose these antigens into vesicles, degrade them, and display peptides bound to class II MHC molecules for recognition by helper T cells. The helper T cells are activated and express CD40L and secrete cytokines, which work together to stimulate the B cells. Many polysaccharide and lipid antigens cannot be recognized by T cells (because they cannot bind to MHC molecules) but have multiple identical antigenic determinants (epitopes) that are able to engage many antigen receptor molecules on each B cell and initiate the process of B-cell activation; these responses are said to be T-independent. T-independent responses are relatively simple, whereas T-dependent responses show features such as Ig isotype switching and affinity maturation (described later), which require T cell help and lead to responses that are more varied and effective.

What is an LE body? What is a LE cell?

In tissues, nuclei of damaged cells react with ANAs, lose their chromatin pattern, and become homogeneous, to produce so-called LE bodies or hematoxylin bodies. Related to this phenomenon is the LE cell, which is readily seen when blood is agitated in vitro. The LE cell is any phagocytic leukocyte (blood neutrophil or macrophage) that has engulfed the denatured nucleus of an injured cell.

How do MHC molecules regulate T cell-mediated immune response

Individual needs to have inherited MHC varient that can bind peptides derived from antigen and present it to T cells. Ex. if you have MHC II against ragweed you'll have an allergic rxn or it can give you resistance to an infection. By segregating cytoplasmic and internalized antigens, MHC molecules ensure that the correct immune response is mounted against different microbes—CTL-mediated killing of cells harboring cytoplasmic microbes and tumor antigens, and helper T cell-mediated antibody production and macrophage activation to combat extracellular and phagocytosed microbes

Why do infections sometimes trigger autoimmunity

Infection -> upregulates expression of costimulators on APCs -> self antigen presented -> breakdown of anergy and activation of self-specific Tcells Some microbes express antigen that share AAs with self antigen -> activates self-reactive lymphocytes aka molecular mimicry (ex.- rheumatic heart disease- streptococcal proteins cross-react with myocardial proteins) EBV and HIV can cause polyclonal B-cell activation -> production of autoantibodies Tissue injury -> structurally-modified self antigen -> neoantigens activate T cells Lack of infection in high income countries -> low-level IL-2 production -> Tregs not maintained -> more autoimmune disease

Define innate vs adaptive immunity

Innate immunity (also called natural, or native, immunity) refers to intrinsic mechanisms that are poised to react immediately, and thus constitute the first line of defense. It is mediated by cells and molecules that recognize products of microbes and dead cells and induce rapid protective host reactions. Adaptive immunity (also called acquired, or specific, immunity) consists of mechanisms that are stimulated by ("adapt to") exposure to microbes and other foreign substances. It develops more slowly than innate immunity, but is even more powerful in combating infections. By convention, the term immune response usually refers to adaptive immunity. The major components of innate immunity are epithelial barriers that block entry of microbes, phagocytic cells (mainly neutrophils and macrophages), dendritic cells, natural killer cells and other innate lymphoid cells, and several plasma proteins, including the proteins of the complement system. Adaptive= B lymphocytes, antibodies, T lymphocytes, effector T cells Innate immunity, unlike adaptive immunity, does not have memory or fine antigen specificity. It is estimated that innate immunity uses about 100 different receptors to recognize 1000 molecular patterns. In contrast, adaptive immunity uses two types of receptors (antibodies and T-cell receptors [TCRs], described later), each with millions of variations, to recognize millions of antigens.

What are innate lymphoid cells

Innate lymphoid cells (ILCs) are tissue-resident lymphocytes that lack T-cell antigen receptors and cannot respond to antigens, but instead are activated by cytokines and other mediators produced at sites of tissue damage. They are thought to be sources of inflammatory cytokines during early phases of immune reactions. ILCs are classified into groups based on the dominant cytokines they produce: groups 1, 2, and 3 ILCs produce many of the same cytokines as Th1, Th2, and Th17 subsets of CD4+ T cells, described later. Natural killer (NK) cells are one type of ILC that provide early protection against many viruses and intracellular bacteria

Isolated IgA deficiency

Isolated IgA deficiency is a common immunodeficiency caused by impaired differentiation of naïve B lymphocytes to IgA-producing plasma cells. Unknow molecular basis but some have b cell activating cytokine (BAFF) receptor defect Most individuals with IgA deficiency are asymptomatic. Because IgA is the major antibody in mucosal secretions, mucosal defenses are weakened, and infections occur in the respiratory, gastrointestinal, and urogenital tracts. Giving blood with IgA causes severe to fatal anaphylactic rxns

Important leukocyte adhesion deficiency facts

LAD 1- defect in the biosynthesis of the β 2 chain shared by the integrins LFA-1 and Mac-1. Leukocyte adhesion deficiency type 2 is caused by the absence of sialyl-Lewis X, the fucose-containing ligand for E- and P-selectins, as a result of a defect in a fucosyl transferase, an enzyme that attaches fucose moieties to protein backbones. Both conditions result in a failure of leukocyte adhesion to endothelium, preventing the cells from migrating into tissues and making patients prone to bacterial infections Chédiak-Higashi syndrome, an autosomal recessive condition characterized by defective fusion of phagosomes and lysosomes, resulting in defective phagocyte function and susceptibility to infections.The dysfunctional gene underlying this disorder encodes a cytosolic protein called LYST, which is believed to regulate lysosomal trafficking. Defects in TLR signaling. Rare defects have been described in various TLRs and their signaling molecules. Defects in TLR3, a receptor for viral RNA, result in recurrent herpes simplex encephalitis, and defects in MyD88, the adaptor protein downstream of multiple TLRs, are associated with destructive bacterial pneumonias.

What is clonal selection

Lymphocytes specific for a large number of antigens exist before exposure to antigen, and when an antigen appears it selectively activates the antigen-specific cells.

Important MHC I facts

MHC 1- on all nucleated cells and platelets. Heterodimer with alpha heavy chain (polymorphic) and smaller beta microglobulin (nonpolymophic). The α chains are encoded by three genes, designated HLA-A, HLA-B, and HLA-C, that lie close to one another in the MHC locus.The extracellular region of the α chain is divided into three domains: α 1 , α 2 , and α 3 . The α 1 and α 2 domains form a cleft, or groove, where peptides bind. The polymorphic amino acid residues line the sides and the base of the peptide-binding groove, explaining why different class I alleles bind different peptides. Class I MHC molecules display peptides that are derived from cytoplasmic proteins, including normal proteins and virus- and tumor-specific antigens, which are all recognized bound to class I MHC molecules by CD8+ T cells. Cytoplasmic proteins are degraded in proteasomes, and peptides are transported into the endoplasmic reticulum (ER), where they bind to newly synthesized class I molecules. Peptide-loaded MHC molecules then associate with β 2 -microglobulin to form a stable complex, which is transported to the cell surface. The nonpolymorphic α 3 domain of class I MHC molecules has a binding site for CD8, and therefore the peptide-class I complexes are recognized by CD8+ T cells, which function as CTLs. In this interaction, the TCR recognizes the MHC-peptide complex, and the CD8 molecule, acting as a coreceptor, binds to the class I heavy chain. CD8+ T cells are class I MHC-restricted because they only recognize peptides if presented as a complex with MHC I

What dye labels mast cells

Mast cells have cytoplasmic membrane-bound granules that contain a variety of biologically active mediators, described later. The granules also contain acidic proteoglycans that bind basic dyes such as toluidine blue. Mast cells and basophils activate by cross-linking high affinity IgE fc receptors. Can be triggered by C5a and C3a (anaphlatoxins) Mast cells and basophils express a high-affinity receptor called FcεRI that is specific for the Fc portion of IgE and avidly binds IgE antibodies. IgE-coated mast cells are said to be sensitized because they are activated by subsequent encounters with antigen. Multivalent antigens bind to and cross-link adjacent IgE antibodies, bringing the underlying Fcε receptors together.

Mechanism of T-cell mediated (type 4) hypersensitivity rxn

Mechanisms of T-cell-mediated (type IV) hypersensitivity reactions. (A) CD4+ Th1 cells (and sometimes CD8+ T cells, not shown ) respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury. CD4+ Th17 cells contribute to inflammation by recruiting neutrophils (and, to a lesser extent, monocytes). (B) In some diseases, CD8+ cytotoxic T lymphocytes directly kill tissue cells. APC, Antigen-presenting cell.

Mechanisms of antibody-mediated injury

Mechanisms of antibody-mediated injury. (A) Opsonization of cells by antibodies and complement components and ingestion by phagocytes. (B) Inflammation induced by antibody binding to Fc receptors of leukocytes and by complement breakdown products. (C) Antireceptor antibodies disturb the normal function of receptors. In these examples, antibodies to the acetylcholine (ACh) receptor impair neuromuscular transmission in myasthenia gravis, and antibodies against the thyroid-stimulating hormone (TSH) receptor activate thyroid cells in Graves disease.

What types of Ig are on naive B cells

Membrane-bound IgM and IgD B cells recognize antigen via the B-cell antigen receptor complex. Membrane-bound antibodies of the IgM and IgD isotypes, present on the surface of all mature, naïve B cells, are the antigen-binding component of the B-cell receptor (BCR) complex. Figure 6.7 Structure of antibodies and the B-cell antigen receptor. (A) The B-cell antigen receptor complex is composed of membrane immunoglobulin M ( IgM; or IgD, not shown ), which recognizes antigens, and the associated signaling proteins Igα and Igβ. CD21 is a receptor for a complement component that also promotes B-cell activation. (B) Crystal structure of a secreted IgG molecule, showing the arrangement of the variable (V) and constant (C) regions of the heavy (H) and light (L) chains.

What is endocrine amyloid

Microscopic deposits of localized amyloid may be found in certain endocrine tumors, such as medullary thyroid carcinoma, pancreatic islet tumor, and pheochromocytoma, and in the islets of Langerhans in individuals with type 2 diabetes mellitus. In these settings, the amyloidogenic proteins seem to be derived either from polypeptide hormones (e.g., medullary carcinoma) or from unique proteins (e.g., islet amyloid polypeptide). In medullary carcinoma of the thyroid, the presence of amyloid is a helpful diagnostic feature.

Severe combined immunodificiency- X-linked SCID

Most common. Male > Female. Mutation in common gamma chain subunit of cytokine receptor. Lots of cytokines are defective consequently (2, 4, 7, 9, 11,15,21). Defective IL-7 signaling -> defect in early lymphocyte (especially T cell) development -> reduced # Tcell. Defective IL-15 signaling -> NK cell deficiency

What is the model for the pathogenesis of systemic lupus erythematosus?

Most system lesions are caused by immune complexes (type 3 hypersensitivity). Renal T-cell inflitrates are often seen. ANAs can enter damaged cells. Also see autoantibodies for WBCs, RBCs, and platelts that cause their opsinization, phagocytosis, and destruction (type 2 rxn; most common is ITP)

Mutations affecting Th1 responses are associated with.... and Th17.....

Mutations affecting Th1 responses are associated with atypical mycobacterial infections; the syndrome is called Mendelian susceptibility to mycobacterial disease . Inherited defects in Th17 responses lead to chronic mucocutaneous candidiasis and bacterial infections of the skin (a disorder called Job syndrome ).

What are Nod-like receptors? What is the inflammasome?

NOD-like receptors (NLRs) are cytosolic receptors named after the founding member NOD-2. They recognize a wide variety of substances, including products released from necrotic or damaged cells (e.g., uric acid and adenosine triphosphate [ATP]), loss of intracellular K + ions, and some microbial products. Several of the NLRs signal via a cytosolic multiprotein complex called the inflammasome, which activates an enzyme (caspase-1) that cleaves a precursor form of the cytokine interleukin-1 (IL-1) to generate the biologically active form. Gain-of-function mutations in NLRs and related proteins, and loss-of-function mutations in regulators of the inflammasome, result in periodic fever syndromes called autoinflammatory syndromes. For example, recognition of urate crystals by a class of NLRs underlies the inflammation associated with gout. These receptors are also capable of detecting lipids and cholesterol crystals that are deposited in abnormally large amounts in tissues, and the resulting inflammation appears to contribute to obesity-associated type 2 diabetes and atherosclerosis, respectively.

How does amyloid accumulate

Normally, misfolded proteins are degraded intracellularly in proteasomes, or extracellularly by macrophages. It appears that in amyloidosis, these quality-control mechanisms fail, leading to accumulation of a misfolded protein outside cells. The proteins that form amyloid fall into two general categories ( Fig. 6.46 ): (1) normal proteins that have an inherent tendency to fold improperly, associate and form fibrils, and do so when they are produced in increased amounts and (2) mutant proteins that are prone to misfolding and subsequent aggregation.

What interleukin is an important autocrine signal for CD4+ helper T cells

One of the earliest responses of CD4+ helper T cells is secretion of the cytokine IL-2 and expression of high-affinity receptors for IL-2. This creates an autocrine loop wherein IL-2 acts as a growth factor that stimulates T-cell proliferation, leading to an increase in the number of antigen-specific lymphocytes. The functions of helper T cells are mediated by the combined actions of CD40-ligand (CD40L) and cytokines. When CD4+ helper T cells recognize antigens being displayed by macrophages or B lymphocytes, the T cells express CD40L, which engages CD40 on the macrophages or B cells and activates these cells.

What do polymorphisms in PTPN22 cause? What about Nod2? What about Il-2 (CD25)?

PTPN22- encodes tyrosine phosphatase. Non-HLA gene most frequently implicated in autoimmunity. Net result is excessive lymphocyte activation NOD2- cytoplasmic snesor of microbes. See entry of commensal bacteria through intestinal epithelium and chronic inflammatory responses Il-2 (CD25)- affects balance between regulatory and effector T cells

Pathogenesis of HIV-1 infection

Pathogenesis of HIV-1 infection. The initial infection starts in mucosal tissues, involving mainly memory CD4+ T cells and dendritic cells, and spreads to lymph nodes. Viral replication leads to viremia and widespread seeding of lymphoid tissue. This corresponds to the early acute phase of HIV infection. The viremia is controlled by the host immune response, and the patient then enters a phase of clinical latency. During this phase, viral replication in both T cells and macrophages continues unabated, but there is some immune containment of virus (not illustrated). There continues a gradual erosion of CD4+ cells, and ultimately CD4+ T-cell numbers decline, and the patient develops clinical symptoms of full-blown AIDS.

Where are patter recognition receptors located

Pattern recognition receptors are located in all cellular compartments where microbes may be present: plasma membrane receptors detect extracellular microbes, endosomal receptors detect ingested microbes, and cytosolic receptors detect microbes in the cytoplasm

How do CTLs kill cell

Perforins and granzymes in lysosome-like granules that enter target cell by endocytosis In the target cell cytoplasm, perforin facilitates the release of the granzymes from the complex. Granzymes are proteases that cleave and activate caspases, which induce apoptosis of the target cells ctivated CTLs also express Fas ligand, a molecule with homology to TNF, which also can trigger apoptosis by binding and activating Fas receptor expressed on target cells.

Primary immune deficiency disease schematic

Primary immune deficiency diseases. Shown are the principal pathways of lymphocyte development and the blocks in these pathways in selected primary immune deficiency diseases. The affected genes are indicated in parentheses for some of the disorders. ADA, Adenosine deaminase; CD40L, CD40 ligand (also known as CD154 ); CVID, common variable immunodeficiency; SCID, severe combined immunodeficiency.

What does AIRE do

Protein that is autoimmune regulator that stimulates expression of some peripheral tissue-restricted self antigens in thymus. It is critical for deletion of immature Tcells specific for these antigens. Patients who have a loss-of-function mutation in AIRE gene can develop autoimmune polyendocrine syndrome -> destruction of multiple endocrin organs n the CD4+ T-cell lineage, some of the cells that see self antigens in the thymus do not die but develop into regulatory T cells

What are examples of T cell mediated diseases

Rheumatoid arthritis, multiple sclerosis, type 1 diabetes, IBD, psoriasis, contact sensitivity

What cellular/cytokine response is associated with granulomatous inflammation

Strong Th1-cell activation and production of IFN-gamma In schistosomiasis the worm eggs elicit a granulomatous rxn that is actually rich in eosinophils and are elicited by a strong Th2 response *typical of many helminthic infections

Describe atopy

Susceptibility to immediate hypersensitivity reactions is genetically determined. A propensity to develop immediate hypersensitivity reactions is called atopy . Atopic individuals tend to have higher serum IgE levels and more IL-4-producing Th2 cells than does the general population. Consider genes for the cytokines IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSF. It is estimated that 20% to 30% of immediate hypersensitivity reactions are triggered by non-antigenic stimuli such as temperature extremes and exercise, and do not involve Th2 cells or IgE; such reactions are sometimes called nonatopic allergy . It is believed that in these cases mast cells are abnormally sensitive to activation by various nonimmune stimuli.

What is serum sickness

Systemic immune complex disease 3 phases: 1) formation of immune complexes- antigen + antibody 2) deposition of immune complexes in vessels. Organs where blood is filtered at high pressure to form other fluids, like urine and synovial fluid, are sites where immune complexes become concentrated and tend to deposit; hence, immune complex disease often affects glomeruli and joints. 3) inflammation and tissue injury due to intiation of acute inflammatory reaction. During active phase C3 is consumed and will lead to decrease in serum activities of C3 In acute serum sickness , caused by a single exposure to a large amount of antigen, the lesions tend to resolve as a result of catabolism of the immune complexes. A form of chronic serum sickness results from repeated or prolonged exposure to an antigen. This occurs in several diseases, such as systemic lupus erythematosus (SLE), which is associated with persistent antibody responses to autoantigens. The Arthus reaction is a localized area of tissue necrosis resulting from acute immune complex vasculitis, usually elicited in the skin. The reaction can be produced experimentally by intracutaneous injection of antigen in a previously immunized animal that contains circulating antibodies against the antigen. As the antigen diffuses into the vascular wall, it binds the preformed antibody, and large immune complexes are formed locally. These complexes precipitate in the vessel walls and cause fibrinoid necrosis, and superimposed thrombosis worsens the ischemic injury.

What is systemic sclerosis (scleroderma)

Systemic sclerosis is characterized by: (1) chronic inflammation thought to be the result of autoimmunity, (2) widespread damage to small blood vessels, and (3) progressive interstitial and perivascular fibrosis in the skin and multiple organs. Some patents with the limited disease develop a combination of calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia, called the CREST syndrome . disease likely results from three interrelated processes—autoimmune responses (CD4+ Tcells, particularly TH2 -> TGF-B and IL-13 PRODUCTION ->transcription of genes encoding collagen and other ECM proteins. Also some ANAs), vascular damage (Repeated cycles of endothelial injury followed by platelet aggregation lead to release of platelet and endothelial factors (e.g., PDGF, TGF-β) that trigger perivascular fibrosis), and collagen deposition (accumulation of alternatively activated macrophages, actions of fibrogenic cytokines produced by infiltrating leukocytes, hyperresponsiveness of fibroblasts to these cytokines, and scarring following ischemic damage caused by the vascular lesions)

Describe T lymphocyte development

T lymphocytes develop in the thymus from precursors that arise from hematopoietic stem cells (HSCs). Mature T cells are found in the blood, where they constitute 60% to 70% of lymphocytes, and in T-cell zones of secondary lymphoid organs (described later). Each T cell recognizes a specific cell-bound antigen by means of an antigen-specific TCR. In approximately 95% of T cells, the TCR consists of a disulfide-linked heterodimer made up of an α and a β polypeptide chain ( Fig. 6.6 ), each having a variable (antigen-binding) region and a constant region. The αβ TCR recognizes peptide antigens that are bound to and presented by major histocompatibility complex (MHC) molecules on the surfaces of antigen-presenting cells (APCs). By limiting the specificity of T cells for peptides displayed by cell surface MHC molecules, called MHC restriction, the immune system ensures that T cells see only cell-associated antigens (e.g., those derived from microbes in cells or from proteins ingested by cells).

Important facts about type IV hypersensitivity

T-cell mediated. Cell-mediated hypersensitivity is caused mainly by inflammation resulting from cytokines produced by CD4+ T cells. Cell killing by CD8+ cells may also be involved in some autoimmune diseases and may be the dominant mechanism of tissue injury in certain reactions, especially those that follow viral infections. Delayed-type hyeprsensitivity-prototype of Type 4 rxns.

What cytokines do mast cells make

TNF, IL-1, and chemokines, which promote leukocyte recruitment (typical of the late-phase reaction); IL-4, which amplifies the Th2 response; and numerous others. The inflammatory cells that are recruited by mast cell-derived TNF and chemokines are additional sources of cytokines.

What does tacrolimus do

Tacrolimus, like its predecessor cyclosporine, is an inhibitor of the phosphatase calcineurin, which is required for activation of a transcription factor called nuclear factor of activated T cells (NFAT). NFAT stimulates transcription of cytokine genes, in particular the gene that encodes the growth factor IL-2. Thus, tacrolimus inhibits T cell responses. Additional drugs that are used to treat rejection include T cell- and B cell-depleting antibodies, and pooled intravenous IgG (IVIG), which suppresses inflammation by unknown mechanisms. Another more recent strategy for reducing antigraft immune responses is to prevent host T cells from receiving costimulatory signals from DCs during the initial phase of sensitization. This can be accomplished by interrupting the interaction between the B7 molecules on the DCs of the graft donor with the CD28 receptors on host T cells, for example, by administration of proteins that bind to B7 costimulators.

What two Thelper cells are abnormal and excessive in most chronic inflammatory diseases

Th1 and Th17 responses are abnormal and excessive in most chronic inflammatory diseases

What does each subset of helper T cell produce

Th1- IFN-gamma. IFN-Y + CD40 = classical macrophage activation Th2- IL-4 (B cells differentiate to IgE-secreting plasma cells) and IL-5 (stimulates eosinopoesis). TH2 also induce allternative pathway of macrophage activation (tissue repair and fibrosis) Th17- IL-17 (recruit neutrophils and monocytes)

What molecules are involved in T-cell activation

The TCR heterodimer, consisting of an α and a β chain, recognizes antigen (in the form of peptide-MHC complexes expressed on antigen-presenting cells, or APCs), and the linked CD3 complex and ζ chains initiate activating signals. CD4 and CD28 are also involved in T-cell activation. (Note that some T cells express CD8 and not CD4; these molecules serve analogous roles.) -Each TCR is noncovalently linked to six polypeptide chains, which form the CD3 complex and the ζ chain dimer. The CD3 and ζ proteins are invariant (i.e., identical) in all T cells. They are involved in the transduction of signals into the T cell that are triggered by binding of antigen to the TCR. Together with the TCR, these proteins form the TCR complex.

What are toll-like receptors and what do they do

The TLRs are present in the plasma membrane and endosomal vesicles. All TLRs signal by a common pathway that culminates in the activation of two sets of transcription factors: (1) NF-κB, which stimulates the synthesis and secretion of cytokines and the expression of adhesion molecules, both of which are critical for the recruitment and activation of leukocytes ( Chapter 3 ), and (2) interferon regulatory factors (IRFs), which stimulate the production of the antiviral cytokines, type I interferons.

What is reactive systmemic amyloidosis

The amyloid deposits in this pattern are systemic in distribution and are composed of AA protein. This category was previously referred to as secondary amyloidosis because it is secondary to an associated inflammatory condition. Could aslo come in association with solid tumors. In this form of amyloidosis, SAA synthesis by liver cells is stimulated by cytokines such as IL-6 and IL-1 that are produced during inflammation; thus, long-standing inflammation leads to a sustained elevation of SAA levels. However, increased production of SAA by itself is not sufficient for the deposition of amyloid. There are two possible explanations for this. According to one view, SAA is normally degraded to soluble end products by the action of monocyte-derived enzymes. Conceivably, individuals who develop amyloidosis have an enzyme defect that results in incomplete breakdown of SAA, thus generating insoluble AA molecules. Alternatively, a genetically determined structural abnormality in the SAA molecule may render it resistant to degradation by macrophages.

What happens when a person is given a TB test

The classic example of DTH is the tuberculin reaction, which is produced by the intracutaneous injection of purified protein derivative (PPD, also called tuberculin), a protein-containing antigen of the tubercle bacillus. In a previously sensitized individual, reddening and induration of the site appear in 8 to 12 hours, reach a peak in 24 to 72 hours, and thereafter slowly subside. Morphologically, delayed-type hypersensitivity is characterized by the accumulation of mononuclear cells, mainly CD4+ T cells and macrophages, around venules, producing perivascular "cuffing" ( Fig. 6.19 ). In fully developed lesions, the venules show marked endothelial hypertrophy, reflecting cytokine-mediated endothelial activation.

What is HLA haplotype

The combination of HLA alleles in each individual is called the HLA haplotype. Any given individual inherits one set of HLA genes from each parent and (assuming the parents are unrelated) typically expresses two different molecules for every locus. This polymorphism is why grafts are rejected

What elements compose the inflammasome

The inflammasome is a protein complex that recognizes products of dead cells and some microbes and induces the secretion of biologically active interleukin 1. The inflammasome consists of a sensor protein (an example is the leucine-rich protein NLRP3), an adapter, and the enzyme caspase-1, which is converted from an inactive to an active form.

Key Concepts for normal immune response

The innate immune system uses several families of receptors (e.g., Toll-like receptors) to recognize molecules present in and shared by various types of microbes and produced by damaged cells. • Lymphocytes are the mediators of adaptive immunity and the only cells that produce specific and diverse receptors for antigens. • T (thymus-derived) lymphocytes express antigen receptors called TCRs that recognize peptide fragments of protein antigens that are displayed by MHC molecules on the surface of antigen-presenting cells. • B (bone marrow-derived) lymphocytes express membrane-bound antibodies that recognize a wide variety of antigens. B cells are activated to become plasma cells, which secrete antibodies. • NK cells destroy cells that are infected by some microbes, or are stressed and damaged beyond repair. NK cells express inhibitory receptors that recognize MHC molecules that are normally expressed on healthy cells, and are thus prevented from killing normal cells. • Antigen-presenting cells (APCs) capture microbes and other antigens, transport them to secondary lymphoid organs, and display them for recognition by lymphocytes. The most efficient APCs are dendritic cells (DCs), which are present in epithelia and most other tissues. • The cells of the immune system are organized in tissues, some of which are the sites of production of mature lymphocytes (the primary, or generative, lymphoid organs, the bone marrow and thymus), and others are the sites of immune responses (the secondary, or peripheral, lymphoid organs, including lymph nodes, spleen, and mucosal lymphoid tissues). • The early reaction to microbes is mediated by the mechanisms of innate immunity, which are always ready to respond to microbes. These mechanisms include epithelial barriers, phagocytes, innate lymphoid cells (ILCs), NK cells, and certain plasma proteins (e.g., the complement system). Innate immune reactions often manifest as inflammation. Innate immunity, unlike adaptive immunity, does not have fine antigen specificity or memory. • The defense reactions of adaptive immunity develop over several days, but are more potent and specialized. • Microbes and other foreign antigens are captured by DCs and transported to lymph nodes, where the antigens are recognized by naïve lymphocytes. The lymphocytes are activated to proliferate and differentiate into effector and memory cells. • Cell-mediated immunity is the reaction of T lymphocytes, designed to combat cell-associated microbes (e.g., phagocytosed microbes and microbes in the cytoplasm of infected cells). Humoral immunity is mediated by antibodies and is effective against extracellular microbes (in the circulation and mucosal lumens). • CD4+ helper T cells help B cells to make antibodies, activate macrophages to destroy ingested microbes, stimulate recruitment of leukocytes, and regulate all immune responses to protein antigens. The functions of CD4+ T cells are mediated by secreted proteins called cytokines. CD8+ cytotoxic T lymphocytes kill cells that express antigens in the cytoplasm that are seen as foreign (e.g., virus-infected and tumor cells) and can also produce cytokines. • Antibodies secreted by plasma cells neutralize microbes and block their infectivity, and they promote the phagocytosis and destruction of pathogens. Antibodies also confer passive immunity to neonates.

What do the following interleukins do: Il-4, IL-5, Il-13

The newly minted Th2 cells produce a number of cytokines on subsequent encounter with the antigen; as mentioned earlier, the signature cytokines of this subset are IL-4, IL-5, and IL-13. IL-4 acts on B cells to stimulate class switching to IgE and promotes the development of additional Th2 cells. IL-5 is involved in the development and activation of eosinophils, which are important effectors of type I hypersensitivity (discussed later). IL-13 enhances IgE production and acts on epithelial cells to stimulate mucus secretion.

What are the 3 major populations of T cells

There are three major populations of T cells, which serve distinct functions. Helper T lymphocytes stimulate B lymphocytes to make antibodies and activate other leukocytes (e.g., phagocytes) to destroy microbes; cytotoxic (killer) T lymphocytes (CTLs) kill infected cells; and regulatory T lymphocytes limit immune responses and prevent reactions against self antigens.

What are the two types of adaptive immunity

There are two types of adaptive immunity: humoral immunity, which protects against extracellular microbes and their toxins, and cell-mediated (or cellular) immunity, which is responsible for defense against intracellular microbes and against cancers. Humoral immunity is mediated by B (bone marrow-derived) lymphocytes and their secreted products, antibodies (also called immunoglobulins , Ig), and cellular immunity is mediated by T (thymus-derived) lymphocytes. Both classes of lymphocytes express highly specific receptors for a wide variety of substances, which are called antigens .

How are eosinophils involved in the late-phase rxn of type 1 hypersensitivity

They are recruited to sites of immediate hypersensitivity by chemokines, such as eotaxin, and others that may be produced by epithelial cells, Th2 cells, and mast cells. The Th2 cytokine IL-5 is the most potent eosinophil-activating cytokine known. Upon activation, eosinophils liberate proteolytic enzymes as well as two unique proteins called major basic protein and eosinophil cationic protein, which damage tissues. Eosniophils contain crystals called Charcot-Leyden crystals composed of the protein galectin-10, which are sometimes released into the extracellular space and can be detected in the sputum of patients with asthma. These crystals promote inflammation and enhance Th2 responses, so they may contribute to allergic reactions.

Common variable immunodeficiency

This relatively frequent entity encompasses a heterogeneous group of disorders in which the common feature is hypogammaglobulinemia, generally affecting all the antibody classes but sometimes only IgG. No single pattern of inheritance. In contrast to X-linked agammaglobulinemia, most individuals with common variable immunodeficiency have normal or near-normal numbers of B cells in the blood and lymphoid tissues. These B cells, however, are not able to differentiate into plasma cells (from intrinsic bcell defect or abnormal thelper-mediated activation). BAFF or ICOS mutation explains few cases. Affects both sexs equally but clinically resembles common variable immunodeficiency. See hyperplastic germinal centers

What major disorder categories of diseases are type 2 hypersensitivities

Transfusion reactions, hemolytic diseseases of newborn/fetus (IgG anti-erythrocyte antibodies), autoimmune hemolytic anemia, agranulocytosis, and thrombocytopenia , and some drug reactions (drugs can even bind to plasma membrane and antibodys can form against drug-protein complexes)

(Another card that doesn't belong) What molecules mediate transmigration of leukocytes vs tight adhesion step

Transmigration= PECAM and CD99 Tight adhesion (necessary to preceed transmigration)= ICAM-1 (interacts with CD11a/CD18 or CD11b/CD18 on leukocytes), VCAM-1 (specific to monocyte and lymphocyte VLA-4), and JAM family

What do regulatory T cells do

Tregs develop mainly in the thymus d/t recognition of self antigen but can be induced in peripheral lymphoid tissue. The best-defined regulatory T cells are CD4+ cells that express high levels of CD25, the α chain of the IL-2 receptor, and FOXP3, a transcription factor of the forkhead family. Both IL-2 and FOXP3 are required for the development and maintenance of functional CD4+ regulatory T cells. Mutation in FOXP3 -> IPEX (systemic autoimmune disease)

What is Wiskott-Aldrich Syndrome? What is ataxia telangtasia?

WAS-progressive loss of Tcells in blood and paracortical areas of lyphnodes. No antibodies to polysaccharide antigens. IgM low. WASP mutation (invovled in cytokeleton-dependent responses) AT- autosomal recessive, ataxia, vascular malformation, neuro defects. defective production of isotype-switched antibodies, mainly IgA and IgG 2 . Thymic hypoplasia. ATM gene deficiency (important for VDJ recombination). Increased lymphoma incidence

What is receptor edition

When developing B cells strongly recognize self antigens in the bone marrow, many of the cells reactivate the machinery of antigen receptor gene rearrangement and begin to express new antigen receptors, not specific for self antigens. This process is called receptor editing ; it is estimated that one-fourth to one-half of all B cells in the body may have undergone receptor editing during their maturation. If receptor editing does not occur, the self-reactive cells undergo apoptosis, thus purging potentially dangerous lymphocytes from the mature pool

What is anergy

When lymphocytes are rendered functionally unresponsive. Activation of antigen-specific T cells requires two signals: recognition of peptide antigen in association with self MHC molecules on the surface of APCs and a set of costimulatory signals ("second signals") from APCs. These second signals are provided by certain T cell-associated molecules, such as CD28, that bind to their ligands (the costimulators B7-1 and B7-2) on APCs. If the antigen is presented to T cells without adequate levels of costimulators, the cells become anergic. Because costimulatory molecules are not expressed or are weakly expressed on resting DCs in normal tissues, the encounter between autoreactive T cells and their specific self antigens displayed by these DCs may lead to anergy.

X-linked agammaglobulinemia

characterized by the failure of B-cell precursors (pro-B cells and pre-B cells) to develop into mature B cells. During normal B-cell maturation in the bone marrow, the Ig heavy-chain genes are rearranged first, in pre-B cells. These form a complex with a "surrogate" light chain on the cell surface called the pre-B cell receptor (pre-BCR) that delivers signals that induce rearrangement of the Ig light-chain genes and further maturation. This need for Ig-initiated signals is a quality-control mechanism that ensures that maturation will proceed only if functional Ig proteins are expressed. X-linked agammaglobulinemia is caused by mutations in a cytoplasmic tyrosine kinase, called Bruton tyrosine kinase (BTK) BTK is a protein tyrosine kinase that is associated with the pre-BCR and with the B-cell receptor (BCR) complexes that are found on mature B cells. When BTK is mutated, the pre-BCR cannot deliver the signals that are needed for light chain rearrangement, and maturation is arrested. BTK is also an important transducer of BCR signals that stimulate growth and increase cell survival in benign and malignant mature B cells seen almost exclusively in men The classic form of this disease has the following characteristics: • B cells are absent or markedly decreased in the circulation, and serum levels of all classes of immunoglobulins are depressed. Pre-B cells, which express the B-lineage marker CD19 but not membrane Ig, are found in normal numbers in the bone marrow. • Germinal centers of lymph nodes, Peyer patches, the appendix, and tonsils are underdeveloped. • Plasma cells are absent throughout the body. • T cell-mediated reactions are normal.

What factor can amyloid bind to and inactivate, causing death

in some cases AL amyloid binds and inactivates factor X, a critical coagulation factor, leading to a life-threatening bleeding disorder. btw: Examination of abdominal fat aspirates stained with Congo red can also be used for the diagnosis of systemic amyloidosis. The test is quite specific, but its sensitivity is low.

What is bare lymphocyte syndrome

is usually caused by mutations in transcription factors that are required for class II MHC gene expression. The lack of class II MHC molecules prevents the development of CD4+ T cells, which are involved in cellular immunity and provide help to B cells; hence, class II MHC deficiency results in combined immunodeficiency

What interleukin drives T cell proliferation

naïve CD4+ T cells recognize peptides displayed by DCs and secrete IL-2, which functions as an autocrine growth factor to stimulate proliferation of the antigen-responsive T cells. The subsequent differentiation of antigen-stimulated T cells to Th1 or Th17 cells is driven by the cytokines produced by APCs at the time of T-cell activation. In some situations, the APCs (DCs and macrophages) produce IL-12, which induces differentiation of CD4+ T cells to the Th1 subset. IFN-γ produced by these effector cells promotes further Th1 development, thus amplifying the reaction. If the APCs produce the inflammatory cytokines IL-1, IL-6, and a close relative of IL-12 called IL-23, the T cells are induced to differentiate to the Th17 subset.

Describe the B-cell antigen receptor complex

the B-cell antigen receptor complex contains a heterodimer of two invariant proteins called Igα and Igβ. Similar to the CD3 and ζ proteins of the TCR complex, Igα (CD79a) and Igβ (CD79b) are essential for signal transduction in response to antigen recognition. B cells also express several other molecules that are essential for their responses. These include the type 2 complement receptor (CR2, or CD21), which recognizes complement products generated during innate immune responses to microbes, and CD40, which receives signals from helper T cells. CR2 is also used by Epstein-Barr virus (EBV) as a receptor to enter and infect B cells.

Describe costimulators

uring the innate response, the microbe or adjuvant activates antigen-presenting cells to express molecules called costimulators and to secrete cytokines that stimulate the proliferation and differentiation of T lymphocytes. The principal costimulators for T cells are the B7 proteins (CD80 and CD86) that are expressed on antigen-presenting cells and are recognized by the CD28 receptor on naïve T cells. Thus, antigen ("signal 1") and costimulatory molecules produced during innate immune responses to microbes ("signal 2") function cooperatively to activate antigen-specific lymphocytes

What are the three most common forms of amyloid

• Amyloid light chain (AL) protein is made up of complete immunoglobulin light chains, the amino-terminal fragments of light chains, or both. Most of the AL proteins analyzed are composed of λ light chains or their fragments, but κ chains are present in some cases. The amyloid fibril protein of the AL type is produced from free Ig light chains secreted by a monoclonal population of plasma cells, and its deposition is associated with certain plasma cell tumors ( Chapter 13 ). • Amyloid-associated (AA) protein is a form of amyloid derived from a unique non-Ig protein made by the liver. The AA protein found in the fibrils is created by proteolysis of a larger precursor called SAA (serum amyloid-associated) protein that is synthesized in the liver and circulates in the blood bound to high-density lipoproteins. The production of SAA protein is increased in inflammatory states as part of the acute phase response; therefore, this form of amyloidosis is associated with chronic inflammation, and is often called secondary amyloidosis. • β-amyloid (Aβ) protein constitutes the core of cerebral plaques found in Alzheimer disease as well as the amyloid deposited in walls of cerebral blood vessels in individuals with this disease. The Aβ protein is derived by proteolysis from a much larger transmembrane glycoprotein called amyloid precursor protein.

Key concepts for amyloidosis

• Amyloidosis is a disorder characterized by the extracellular deposits of misfolded proteins that aggregate to form insoluble fibrils. • The deposition of these proteins may result from: excessive production of proteins that are prone to misfolding and aggregation; mutations that produce proteins that cannot fold properly and tend to aggregate; and defective or incomplete proteolytic degradation of extracellular proteins. • Amyloidosis may be localized or systemic. It is seen in association with a variety of primary disorders, including monoclonal B-cell proliferations (in which the amyloid deposits consist of immunoglobulin light chains); chronic inflammatory diseases such as rheumatoid arthritis (deposits of amyloid A protein, derived from an acute-phase protein produced in inflammation); Alzheimer disease (amyloid β protein); familial conditions in which the amyloid deposits consist of mutants of normal proteins (e.g., transthyretin in familial amyloid polyneuropathies); and amyloidosis associated with dialysis (deposits of β 2 -microglobulin, whose clearance is defective). • Amyloid deposits cause tissue injury and impair normal function by causing pressure on cells and tissues. They do not evoke an inflammatory response.

Key concepts for pathogenesis of diseases caused by antibodies and immune complexes

• Antibodies can coat (opsonize) cells, with or without complement proteins, and target these cells for phagocytosis by phagocytes (macrophages), which express receptors for the Fc tails of lgG and for complement proteins. The result is depletion of the opsonized cells. • Antibodies and immune complexes may deposit in tissues or blood vessels and elicit an acute inflammatory reaction by activating complement, with release of breakdown products, or by engaging Fc receptors of leukocytes. The inflammatory reaction causes tissue injury. • Antibodies can bind to cell surface receptors or other essential molecules and cause functional derangements (either inhibition or unregulated activation) without cell injury.

Key concepts for mechanisms of T cell-mediated hypersensitivity rxn

• Cytokine-mediated inflammation: CD4+ T cells are activated by exposure to a protein antigen and differentiate into Th1 and Th17 effector cells. Subsequent exposure to the antigen results in the secretion of cytokines. IFN-γ activates macrophages to produce substances that cause tissue damage and promote fibrosis, and IL-17 and other cytokines recruit leukocytes, thus promoting inflammation. The classical T cell-mediated inflammatory reaction is DTH. • T cell-mediated cytotoxicity: CD8+ cytotoxic T lymphocytes (CTLs) specific for an antigen recognize cells expressing the target antigen and kill these cells. CD8+ T cells also secrete IFN-γ.

What are the 4 types of hypersensitivity reaction

• In immediate hypersensitivity (type I hypersensitivity) , the injury is caused by Th2 cells, IgE antibodies, and mast cells and other leukocytes. Mast cells release mediators that act on vessels and smooth muscle and proinflammatory cytokines that recruit inflammatory cells. • In antibody-mediated disorders (type II hypersensitivity) , secreted IgG and IgM antibodies injure cells by promoting their phagocytosis or lysis and injure tissues by inducing inflammation. Antibodies may also interfere with cellular functions and cause disease without tissue injury. • In immune complex-mediated disorders (type III hypersensitivity) , IgG and IgM antibodies bind antigens usually in the circulation, and the antigen-antibody complexes deposit in tissues and induce inflammation. The leukocytes that are recruited (neutrophils and monocytes) produce tissue damage by release of lysosomal enzymes and generation of toxic free radicals. • In cell-mediated immune disorders (type IV hypersensitivity) , T lymphocytes (Th1 and Th17 cells and CD8+ CTLs) are the cause of the tissue injury.

How do macrophages interact with T cells

• Macrophages that have phagocytosed microbes and protein antigens process the antigens and present peptide fragments to T cells. Thus, macrophages function as antigen-presenting cells in T-cell activation. • Macrophages are key effector cells in certain forms of cell-mediated immunity, the reaction that serves to eliminate intracellular microbes. In this type of response, T cells activate macrophages and enhance their ability to kill ingested microbes (discussed later). • Macrophages also participate in the effector phase of humoral immunity. Macrophages efficiently phagocytose and destroy microbes that are opsonized (coated) by IgG or C3b.

What is Sjogren syndrome

• Sjögren syndrome is an inflammatory disease that affects primarily the salivary and lacrimal glands, causing dryness of the mouth and eyes. • The disease is believed to be caused by an autoimmune T-cell reaction against an unknown self antigen expressed in these glands, or immune reactions against the antigens of a virus that infects the tissues.

Key concepts about recognition and rejection of transplants (allografts)

• The rejection response against solid organ transplants is initiated mainly by host T cells that recognize the foreign HLA antigens of the graft, either directly (on APCs in the graft) or indirectly (after uptake and presentation by host APCs). • Types and mechanisms of rejection of solid organ grafts: • Hyperacute rejection. Preformed antidonor antibodies bind to graft endothelium immediately after transplantation, leading to thrombosis, ischemic damage, and rapid graft failure. • Acute cellular rejection. T cells destroy graft parenchyma (and vessels) by cytotoxicity and inflammatory reactions. • Acute humoral rejection. Antibodies damage graft vasculature. • Chronic rejection. Dominated by arteriosclerosis, this type is caused by T-cell activation and antibodies. The T-cells may secrete cytokines that induce proliferation of vascular smooth muscle cells, and the antibodies cause endothelial injury. The vascular lesions and T-cell reactions cause parenchymal fibrosis. • Treatment of graft rejection relies on immunosuppressive drugs, which inhibit immune responses against the graft. • Transplantation of HSCs requires careful matching of donor and recipient and is often complicated by GVHD and immune deficiency.

Key concepts for immediate (type 1) hypersensitivity

• These are also called allergic reactions, or allergies. • They are induced by environmental antigens (allergens) that stimulate strong Th2 responses and IgE production in genetically susceptible individuals. • IgE attaches to mast cells by binding to Fcε receptors; reexposure to the allergen leads to cross-linking of the IgE and FcεRI, activation of mast cells, and release of mediators. • The principal mediators are histamine, proteases, and other granule contents; prostaglandins and leukotrienes; and cytokines. • The mediators are responsible for the immediate vascular and smooth muscle reactions and the late-phase reaction (inflammation). • The clinical manifestations may be local or systemic, and range from mildly annoying rhinitis to fatal anaphylaxis.

Key concepts for primary (inherited) immunodeficiencies

• These diseases are caused by inherited mutations in genes involved in lymphocyte maturation or function, or in innate immunity. • Deficiencies in innate immunity include defects of phagocyte function, complement, and innate immune receptors. • Some of the common disorders affecting lymphocytes and the adaptive immune response are: • X-SCID: failure of T-cell and B-cell maturation; mutation in the common γ chain of a cytokine receptor, leading to failure of IL-7 signaling and defective lymphopoiesis • Autosomal recessive SCID: failure of T-cell development, secondary defect in antibody responses; approximately 50% of cases caused by mutation in the gene encoding ADA, leading to accumulation of toxic metabolites during lymphocyte maturation and proliferation • X-linked agammaglubulinemia: failure of B-cell maturation, absence of antibodies; caused by mutations in the BTK gene, which encodes B-cell tyrosine kinase, required for maturation signals from the pre-BCRs and BCRs • Common variable immunodeficiency: defects in antibody production; cause unknown in most cases • Selective IgA deficiency: failure of IgA production; cause unknown • X-linked hyper-IgM syndrome: failure to produce isotype-switched high-affinity antibodies (IgG, IgA, IgE); mutation in gene encoding CD40L • X-linked lymphoproliferative disease: defect in a signaling molecule causing defective responses against Epstein-Barr virus and lymphoproliferation

Key concepts for immunologic tolerance and autoimmunity

• Tolerance (unresponsiveness) to self antigens is a fundamental property of the immune system, and breakdown of tolerance is the basis of autoimmune diseases. • Central tolerance: immature lymphocytes that recognize self antigens in the central (generative) lymphoid organs are killed by apoptosis; in the B-cell lineage, some of the self-reactive lymphocytes switch to new antigen receptors that are not self-reactive. • Peripheral tolerance: mature lymphocytes that recognize self antigens in peripheral tissues become functionally inactive (anergic) or are suppressed by regulatory T lymphocytes, or they die by apoptosis. • The factors that lead to a failure of self-tolerance and the development of autoimmunity include (1) inheritance of susceptibility genes that may disrupt different tolerance pathways and (2) infections and tissue injury that may expose self antigens and activate APCs and lymphocytes in the tissues. • Autoimmune diseases are usually chronic and progressive, and the type of tissue injury is determined by the nature of the dominant immune response.