Download path 184 to 226 Innate Immunity Innate immunity: epithelial barriers

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Innate Immunity
 Innate immunity: epithelial barriers, phagocytic cells (neutrophils and macrophages), DCs, NKs, plasma proteins
 Cellular reactions: inflammation (phagocytic leukocytes recruited and activated to kill microbes) and anti-viral
defense (mediated by DCs and NKs)
 Pathogen-associated molecular patterns: components of microbes essential for infectivity (thus can’t mutate);
leukocytes and epithelial cells recognize these to initiate immune response
 Danger-associated molecular patterns: molecules released by injured and necrotic cells; WBCs recognize these
 Different TLRs specific for components of different bacteria and viruses
o Signal by common pathway that leads to activation of transcription factors (NF-κB), which turns on
production of cytokines and proteins that stimulate microbicidal activities of various cells
 Receptors for mannose residues and receptors for opsonins: bind microbes for phagocytosis
 Dendritic cells – produce type I interferons (anti-viral cytokines that inhibit viral infection and replication)
 Complement system activated by microbes using alternative and lectin pathways
 Mannose-binding lectin and C-reactive protein coat microbes for phagocytosis
Adaptive Immunity
 Complement system activated by antibodies using classical pathway
 Adaptive immunity = Lymphocytes and their products
Cells of the Immune System
 Lymphocytes differentiate into effector cells (perform function) and memory cells
 T cells: 60-70% of lymphocytes in blood; recognizes specific cell-bound antigen by means of TCR
o TCR consists of α and β chains (disulfide-linked); recognizes peptide antigens displayed by MHC on
surface of APCs (MHC restriction)
o During T cell development in thymus, TCR genes rearrange to form different combos
 Enzyme that mediates rearrangement is product of RAG-1 and RAG-2; mutations in these genes
result in failure to generate mature lymphocytes
o Polyclonal T cell clusters non-neoplastic; monoclonal T-cell proliferations neoplastic
o Each TCR noncovalently linked to 5 polypeptide chains that form CD3 complex and ζ chain dimer
(identical in all T cells); involved in transduction of signals into T cell after TCR binds antigen
o TCR complex = TCR + CD3 + ζ chain dimer
o γδ TCR recognizes peptides, lipids, and small molecules w/o required MHC; aggregate at epithelial
surfaces
o NK-T cells – very limited diversity of TCRs; recognize glycolipids displayed by MHC-like molecule CD1
o CD4 and CD8 expressed on mutually exclusive subsets of αβ T cells; serve as coreceptor that initiates
signals necessary for activation of T cells
 CD4+ function as cytokine-secreting helper cells that help macrophages and B cells; respond to
class II MHC molecules
 CD8+ are CTLs; respond to class I MHC molecules
 B lymphocytes: develop from precursors in bone marrow; present in blood, lymph nodes, spleen, and MALT
o Recognize antigen via B-cell antigen receptor complex
o Membrane-bound antibodies (IgM and IgD) on surface of naïve B cells; antigen-binding component of
receptor complex; receptors have specificity derived from RAG-mediated rearrangement of Ig genes
o Antigen receptor complex also contains Igα and Igβ; essential for signal transduction through antigen
receptor
o Type 2 complement receptor (CR2 or CD21) is receptor for EBV, which readily infects B cells
o Have Fc receptors, complement receptors, and CD40
 Dendritic cells (interdigitating dendritic cells): most important APC for initiating primary T-cell responses
o Located under epithelial and interstitial of all tissues
o Langerhans cell – immature DC in epidermis
o Express TLRs and mannose receptors to bind antigens
o DCs recruited to T-cell zones of lymphoid organs, where they present antigens to T cells
o Express high levels of molecules needed for presenting antigens to and activating CD4+ T cells
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Follicular dendritic cells – bear Fc receptors for IgG and receptors for C3b; can trap antigen bound to antibodies
or complement proteins
o Present antigens to B cells and select B cells w/highest affinity for antigen
 Macrophages that have phagocytosed microbes and protein antigens process antigens and present peptide
fragments to T cells
o T cells activate macrophages and enhance ability to kill ingested microbes
o Participate in effector phase of humoral immunity (phagocytose opsonized microbes w/IgG or C3b)
 NK cells: 10-15% of peripheral blood lymphocytes; contain abundant azurophilic granules (large granular
lymphocytes)
o Kill infected and tumor cells w/o prior exposure or activation
o CD16 (Fc receptor for IgG; confers ability to lyse IgG-coated target cells [antibody-dependent cellmediated cytotoxicity; ADCC]) and CD56 commonly used to identify NK cells
o Functional activity of NK cells regulated by balance between signals from activating and inhibitory
receptors
o NKG2D receptors recognize surface molecules induced by stress (infection, DNA damage)
o Inhibitor receptors recognize self-class I MHC molecules expressed on all healthy cells (either Ig-like
receptors or CD94 family of lectins); prevent NK cell from killing normal cells
 Infection or neoplastic transformation induces expression of ligands for activating receptors and
reduces expression of class I MHC molecules
o Secrete IFN-γ, which activates macrophages to destroy ingested microbes
o Activity regulated by interleukins (IL-2 & IL-15 stimulate proliferation of NKs; IL-12 activates killing
function and secretion of IFN-γ)
Tissues of the Immune System
 Generative lymphoid organs – thymus and bone marrow
 Peripheral lymphoid organs – lymph nodes, spleen, and mucosal and cutaneous lymphoid tissues; organized to
concentrate antigens, APCs, and lymphocytes to optimize interactions and adaptive immune responses
o Spleen – reacts to blood-borne antigens; blood flows through sinusoids, and antigens trapped by DCs
and macrophages in spleen
 T lymphocytes concentrated periarteriolar lymphoid sheaths surrounding small arterioles
 B cells in follicles
o Cutaneous lymphoid system under epithelial of skin; mucosal lymphoid system under epithelia of GI and
respiratory tracts
 Pharyngeal tonsils and Peyer’s patches are mucosal lymphoid tissues
o In lymph nodes, B cells concentrated in discrete structures (follicles) in periphery (cortex); if B cell
recently responded to antigen, follicle may contain germinal center
 T cells concentrated in paracortex (adjacent to follicles)
 Follicles contain follicular DCs, and paracortex contains DCs presenting to T cells
 Location of cells in follicles or paracortical areas dictated by chemokines produced by
lymphocytes there; causes lymphocytes to leave lymph node and migrate to help
 Lymphocytes constantly recirculate between tissues and home (lymph nodes)
o Naïve lymphocytes traverse peripheral lymphoid organs where immune responses initiated
o Effector lymphocytes migrate to site of infection and inflammation
o Plasma cells remain in lymphoid organs and don’t need to go to actual inflammation site
o Naïve T cells migrate to lymph nodes and enter T-cell zones through high endothelial venules (HEVs)
 In lymph node, naïve cell encounters antigen that it specifically recognizes on APC
 Activates and alters expression of adhesion molecules and chemokine receptors
 Differentiated effector T cells leave lymph nodes, enter circulation, and migrate to tissues that
harbor microbes
Major Histocompatibility Complex (MHC) Molecules
 Displays peptide fragments of proteins for recognition by antigen-specific T cells
 Genes for MHC molecules clustered in HLA complex
 Class I MHC molecules – expressed on all nucleated cells and platelets; encoded by HLA-A, HLA-B, and HLA-C
o Each molecule: polymorphic α (heavy) chain linked to non-PM β2-microglobulin not encoded in MHC
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Extracellular region of α chain divided into 3 domains (α1, α2, α3); 1 & 2 form cleft where peptides bind
Polymorphic residues line sides and base of peptide-binding groove; variation why binds diff. peptides
Display peptides derived from proteins (viral antigens) located in cytoplasm; proteins degraded in
proteasomes, peptides transported to ER, where they bind to newly synthesized class I molecules
 Peptide-loaded MHC molecules w/β2-microglobulin form stable trimer transported to PM
o Nonpolymorphic α3 domain has binding site for CD8
o TCR recognizes MHC-peptide complex; CD8 molecule binds to class I heavy chain
 Class II MHC molecules – encoded by HLA-D (subregions: HLA-DP, HLA-DQ, HLA-DR)
o Each has polymorphic α and β chains, each w/2 domains
o Peptide-binding cleft formed by α1 and β1 domains; place where alleles differ
o Present antigens that are internalized into vesicles; typically derived from extracellular microbes and
soluble proteins
 Internalized proteins proteolytically digested in endosomes or lysosomes
 Peptides from lysosomes associate w/class II heterodimers in vesicles; stable peptide-MHC
complexes transported to PM
 Class II β2 domain has binding for CD4
o Mainly expressed in macrophages, B lymphocytes, and DCs
 MHC locus contains genes that encode some complement components, TNF, and lymphotoxin
o Class II locus contains genes that encode proteins involved in antigen processing and presentation
(components of proteasome, peptide transporter, and class II-like molecule (DM) that facilitates peptide
binding to class II molecules)
 Combo of HLA alleles in person = HLA haplotype; one set of genes from each parent = expression of 2 different
molecules for every locus
 These are what are seen as foreign in transplanted organs
 Those that inherit HLA-B27 have much greater risk of ankylosing spondylitis
 Diseases associated w/HLA locus
o Inflammatory diseases: ankylosing spondylitis and several postinfectious athropathies (HLA-B27)
o Autoimmune diseases (endocrinopathies) associated w/alleles at DR locus
o Inherited errors of metabolism (21-hydroxylase deficiency by HLA-BW47 and hereditary
hemochromatosis by HLA-A)
Cytokines: Messenger Molecules of the Immune System
 Interleukins: cytokines that mediate communication between leukocytes
 Cytokines of innate immunity: produced rapidly in response to microbes and other stimuli; made principally by
macrophages, DCs, and NK cells; mediate inflammation and anti-viral defense
o Include TNF, IL-1, IL-12, type I IFNs, IFN-γ, and chemokines
 Cytokines of adaptive immune responses: made principally by CD4+ T lymphocytes in response to antigen and
other signals; function to promote lymphocyte proliferation and differentiation and activate effector cells
o IL-2, IL-4, IL-5, IL-17, and IFN-γ
 Colony-stimulating factors: stimulate hematopoiesis; increase WBC numbers during immune and inflammatory
responses and replace WBCs consumed during responses
 TNF antagonists can improve RA Sx
Display and Recognition of Antigens
 Lymphocytes specific for large number of antigens exist before exposure to antigen; when antigen enters, it
selects specific cells and activates them (clonal selection hypothesis)
 During innate response, microbe activates APCs to express molecules (costimulators) and secrete cytokines that
stimulate proliferation and differentiation of T lymphocytes
o Principal costimulators are B7 proteins (CD80 and CD86) expressed on APCs; recognized by CD28
receptor on naïve T cells
o Antigen = signal 1; costimulatory molecules produced during innate immune response = signal 2
 Signal 2 can be provided by substances released from necrotic cells (danger-associated mol.)
Cell-Mediated Immunity: Activation of T Lymphocytes and Elimination of Intracellular Microbes
 One of earliest responses of CD4+ T cells is secretion of IL-2 and expression of high-affinity receptors for IL-2
o IL-2 acts on T cells and stimulates proliferation, leading to increase in antigen-specific lymphocytes
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Functions of CD4+ T cells mediated by combined actions of CD40L (expressed on CD4+ cell when it
recognizes displayed antigens) and cytokines
o Some progeny of expanded T cells differentiate into effector cells that secrete different sets of cytokines
 TH1 secretes IFN-γ (potent macrophage activator)
 TH2 secretes IL-4 (stimulates B cells to differentiate into IgE-secreting plasma cells) and IL-5
(activates eosinophils)
 TH17 secretes IL-17; recruits neutrophils and monocytes
Humoral Immunity: Activation of B Lymphocytes and Elimination of Extracellular Microbes
 When activated, B cells proliferate and differentiate into plasma cells that secrete different classes of antibodies
 Many antigens have multiple identical antigenic determinants (epitopes) able to engage antigen receptor
molecules on each B cell and initiate process of B-cell activation
 Typical globular protein antigens not able to bind to antigen receptors; full response of B cells to protein
antigens requires CD4+ T cells
 B cells ingest protein antigens into vesicles, degrade them, and display peptides bound to MHC molecules for
recognition by CD4+ T cells, which express CD40L and secrete cytokines to active B cells
 Each plasma cell secretes antibodies that have same antigen binding site as cell surface antibodies
o Polysaccharides and lipids stimulate secretion mainly of IgM antibody
o Protein antigens (by virtue of CD40L and cytokine-mediated CD4+ T cell actions) induce production of
antibodies of different isotypes (IgG, IgA, IgE)
o Cytokines (IFN-γ, IL-4) induce isotype switching
o CD4+ T cells stimulate production of antibodies w/high affinities for antigen (affinity maturation)
o Isotype switching and affinity maturation occur mainly in germinal centers (formed by proliferating B
cells), esp. in helper T cell-dependent responses to protein antigens
 Antibodies bind to microbes and prevent them from infecting cells (neutralizing)
o IgG antibodies opsonize microbes (neutrophils and macrophages express receptors for Fc tails of IgG
o IgG and IgM activate complement system by classical pathway; complement products promote
phagocytosis and destruction of microbes
o IgA secreted from mucosal epithelia neutralizes microbes in lumen of respiratory and GI tract
o IgG actively transported across placenta and protects newborn until immune system mature
o IgE and eosinophils cooperate to kill parasites
 Some antibody-secreting plasma cells migrate to bone marrow and liver for years, producing low Ig levels
Decline of Immune Responses and Immunological Memory
 Majority of effector lymphocytes induced by infectious pathogen die by apoptosis after microbe eliminated
 Initial activation of lymphocytes generates long-lived memory cells (expanded pool of antigen-specific
lymphocytes; more numerous than naïve cells specific for any antigen); respond faster and more effectively
when re-exposed to antigen than naïve cells
Mechanisms of Hypersensitivity Reactions
 Hypersensitivity – excessive response due to repeat exposure to antigen; pathologic response
 Development of hypersensitivity diseases associated w/inheritance of particular susceptibility genes
 Reflects imbalance between effector mechanisms of immune responses and control mechanisms that serve to
normally limit responses
 Type I (immediate): immune response mediated by TH2 cells, IgE, and mast cells; results in release of mediators
(act on vessels/smooth muscle) & pro-inflammatory cytokines (recruit inflammatory cells)
o Occurs in minutes after combo of antigen w/antibody bound to mast cells in previously sensitized pt
o Immediate (initial) reaction  vasodilation, vascular leakage, and sm. muscle spasm or gland secretions
o Late-phase reaction  infiltration of tissues w/eosinophils, neutrophils, basophils, monocytes, and CD4+
T cells; tissue destruction typically mucosal epithelial cell damage
o Most rxns mediated by IgE antibody-dependent activation of mast cells and other WBCs
 Mast cell: bone-marrow-derived cell widely distributed in tissues (nearest blood vessels, nerves,
and subepithelial tissues)
 PM-bound granules that contain active mediators & acidic proteoglycans
 Activated by cross-linking of high-affinity IgE Fc receptors
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Triggered by C5a and C3a (anaphylatoxins), which bind receptors on mast PM
Multivalent antigens bind to and cross-link adjacent IgE antibodies and underlying FcεRI,
activating signal transduction pathways from cytoplasmic portion of receptors, leading
to mast cell degranulation w/discharge of preformed (primary) mediators stored in
granules and de novo synthesis and release of secondary mediators
 Basophils: surface IgE Fc receptors and cytoplasmic granules
 Mast cells and basophils have FcεRI (specific for Fc portion of IgE) that binds IgE
o TH2 cells stimulate IgE production and promote inflammation
 Antigen presented to naïve CD4+ T cell; in response to antigen and IL-4, T cell differentiates into
TH2 cell, which produces cytokines upon subsequent encounter w/antigen
 IL-4 stimulates class switching to IgE in B cells; promotes development of more TH2
 IL-5 involved in development and activation of eosinophils
 IL-13 enhances IgE productin and acts on epithelial cells to stimulate mucus secretion
 More chemokines that attract more TH2 cells as well as other WBCs
o Preformed mediators
 Vasoactive amines: histamine; causes intense smooth muscle contraction, increased vascular
permeability, and increased mucus secretion by nasal, bronchial, and gastric glands
 Enzymes: neutral proteases (chymase, tryptase) and acid hydrolases; contained in granule
matrix; cause tissue damage and lead to generation of kinins and activated complement
components (C3a) by acting on precursor proteins
 Proteoglycans: include heparin and chondroitin sulfate; package and store amines in granules
o Lipid mediators: synthesized by sequential rxns in mast PMs that lead to activation of phospholipase A2
(acts on membrane phospholipids to yield arachidonic acid)
 Leukotrienes C4 and D4 (most potent vasoactive and spasmogenic agents known); leukotriene B4
highly chemotactic for neutrophils, eosinophils, and monocytes
 Prostaglandin D2: most abundant mediator produced in mast cells by COX pathway; causes
intense bronchospasm and increased mucus secretion
 Platelet-activating factor (PAF): produced by some mast cells; causes platelet aggregation,
release of histamine, bronchospasm, increased vascular permeability, and vasodilation
 Chemotactic for neutrophils and eosinophils
 At high concentrations, activates inflammatory cells to degranulate
o Cytokines: histamine and leukotrienes responsible for intense immediate rxn (edema, mucus secretin,
SM spasm); cytokines recruit additional WBCs
o Eosinophils: recruited by chemokines (eotaxin) produced by epithelial cells, TH2 cells, and mast cells
 Survival in tissues favored by IL-3, IL-5 (most potent), and GM-CSF
 Liberate proteolytic enzymes, major basic protein, & eosinophil cationic protein (toxic to
epithelial cells)
 Produce C4 and PAF; directly activate mast cells to release mediators; recruited cells amplify and
sustain inflammatory response w/o additional exposure to triggering antigen (major cause of Sx
in allergic asthma); use steroids to treat
o Atopy: predisposition to develop localized immediate hypersensitivity reactions to allergens; genetic
 Atopic people have higher serum IgE levels and more IL-4-producing TH2 cells
o Can be triggered by temp extremes or exercise (non-atopic allergy because no TH2 or IgE)
Type II (antibody-mediated): secreted IgG and IgM antibodies to antigens on cell surfaces or ECM participate
directly in injury to cells by promoting phagocytosis or lysis; injury to tissues by induced inflammation
o Antibodies may interfere w/cellular functions and cause disease w/o tissue injury (myasthenia gravis
[inhibitory receptor response] or Graves disease [stimulatory receptor response])
o Cells opsonized by IgG recognized by phagocyte Fc receptors
o When IgM or IgG deposited on surface of cell, they can activate complement system (classic path); C3b
and C4b deposited on surfaces of cells and recognized by phagocytes that express receptors for proteins
 Complement activation leads to formation of membrane attack complex (drills holes through
lipid bilayer, causing osmotic lysis); effective only w/cells w/thin walls (Neisseria)
o ADCC: cells coated w/low concentrations of IgG killed by effector cells that bind to target by Fc receptors
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Lysis w/o phagocytosis; mediated by monocytes, neutrophils, eosinophils, and NK cells
Occurs in transfusion reaction; hemolytic disease of newborn (erythroblastosis fetalis; antigenic
difference between mother and fetus); autoimmune hemolytic anemia, agranulocytosis, and
thrombocytopenia (antibodies to own blood cells); and certain drug reactions (drug acts as
hapten by attaching to surface molecules of RBCs and antibodies produced against drugmembrane protein complex)
o When antibodies deposit in fixed tissues, injury due to inflammation; deposited antibodies activate
complement, generating by-products, including chemotactic agents (C5a; directs migration of PMNs and
monocytes) and anaphylatoxins (C3a and C5a; increase vascular permeability)
 WBCs activated by engagement of C3b and Fc receptors; results in release or generation of
prostaglandins, vasodilator peptides, and chemotactic substances
 WBC activation leads to production of lysosomal enzymes (proteases) that digest BM, collagen,
elastin, and cartilage; produce ROS
o Mechanism responsible for glomerulonephritis, vascular rejection of organ grafts
Type III (immune complex-mediated): IgG and IgM antibodies bind antigens in circulation; complexes deposit in
tissues and induce inflammation; neutrophils and monocytes produce damage by release of lysosomal enzymes
and generation of toxic free radicals
o Sometimes complexes formed at extravascular sites where antigen may have planted previously (in situ
immune complexes)
o Acute serum sickness: formation of antigen-antibody complex in circulation, deposition of complex in
tissue, initiating inflammatory reaction at sites of immune complex deposition
o Complexes of medium size formed in slight antigen excess are most pathogenic
o Organs where blood filtered at high pressure to form other fluids (urine, synovial fluid) favored
o Vasculitis – inflammatory lesion in blood vessels
o Morphology: principal manifestation is acute necrotizing vasculitis w/necrosis of vessel wall and intense
neutrophilic infiltration
 Necrotic tissue and deposits produce smudgy eosinophilic deposit that obscures underlying
cellular detail (fibrinoid necrosis)
 Granular lumpy deposits of Ig and complement in kidney (glomerulonephritis)
o If disease from single large exposure to antigen (acute serum sickness), lesions resolve from catabolism
of immune complexes
o Chronic form results from repeated or prolonged exposure (SLE)
o Arthus reaction: localized area of tissue necrosis resulting from acute immune complex vasculitis
 Can be produced experimentally via scratch test
 As antigen diffuses into vascular wall, it binds preformed antibody, and large immune complexes
formed locally; precipitates in vessel walls and causes fibrinoid necrosis; superimposed
thrombosis worsens ischemic injury
Type IV (cell-mediated): sensitized T lymphocytes (TH1, TH17, and CTLs) cause cellular and tissue injury
o Can be cause of chronic inflammatory disease
o Delayed-type hypersensitivity (DTH): CD4+ T cells; sometimes called immune inflammation
 TH1 and TH17 cells contribute to organ-specific diseases where inflammation prominent
 TH1 reaction dominated by activated macrophages; TH17 rxn has more neutrophils
 TH1 cells secrete IFN-γ, which activates macrophages (ability to phagocytose and kill
microorganisms augmented; express more class II MHC molecules on surface; secrete TNF, IL-1,
and chemokines that promote inflammation; produce more IL-12, amplifying TH1 response)
 Activated TH17 secrete IL-17, IL-22, chemokines, and several other cytokines that recruit
neutrophils and monocytes, promoting inflammation; TH17 secretes IL-21 that amplifies TH17 rxn
 Tuberculin reaction produced by PPD (tuberculin); DTH characterized by accumulation of
mononuclear cells (CD4+ T cells and macrophages) around venules, producing perivascular
cuffing; in fully developed lesion, venules show marked endothelial hypertrophy
 Tubercle bacilli in lungs: perivascular infiltrate dominated by macrophages for 2-3 wks; activated
macrophages undergo morphologic transformation into epithelium-like cells (epithelioid cells)
surrounded by collar of lymphocytes (granuloma)
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Contact dermatitis: evoked by contact w/urushiol (antigenic component of poison ivy & poison
oak); presents as vesicular dermatitis
o Cell-mediated cytotoxicity: CD8+ CTLs kill antigen-bearing target cells; can cause DM type 1
 Directed against MHC antigens in graft rejection
 Perforins and granzymes – preformed mediators in lysosome-like granules of CTLs
 CTLs that recognize target cells secrete complex of perforin, granzymes, and serglycin
(enters target cells by endocytosis)
 In cytoplasm, perforin facilitates release of granzymes from complex
 Granzymes cleave and activate caspases (induce apoptosis)
 Activated CTLs express Fas ligand that binds Fas expressed on target cells and triggers apoptosis
 Produce cytokines (IFN-γ) involved in inflammatory reactions resembling DTH
Autoimmune Diseases
 3 requirements to be classified autoimmunity
o Presence of immune reaction specific for some self-antigen or self-tissue
o Evidence that such reaction not secondary to tissue damage but is of primary pathogenic significance
o Absence of another well-defined cause of the disease
 Immune-mediated inflammatory diseases – uncertainty about target antigens and contribution of true
autoimmunity; emphasizes chronic inflammation as part of pathogenesis
 Immunological tolerance – unresponsiveness to antigen as result of exposure of lymphocytes to that antigen
 Central tolerance: immature self-reactive B and T clones that recognize self-antigens during maturation in
lymphoid organs are killed or rendered harmless
o When immature T cells encounter antigens in thymus, cells that express self-antigen receptors die by
apoptosis (negative selection, deletion)
 AIRE stimulates expression of peripheral tissue-restricted self-antigens in thymus; critical for
deletion of immature T cells specific for antigens
 Mutations in AIRE gene cause autoimmune polyendocrinopathy
o When developing B cells strongly recognize self-antignes, many reactivate machinery of antigen
receptor gene rearrangement to get different receptors (receptor editing)
 If receptor editing doesn’t occur, self-reactive cells undergo apoptosis
 Peripheral tolerance: silencing autoreactive B and T cells in peripheral tissues
o Anergy – prolonged or irreversible functional inactivation of lymphocytes, induced by encounter
w/antigens under certain conditions
 If antigen presented by cells that dono’t bear costimulators, negative signal delivered, and cell
becomes anergic
 Mechanisms: cells lose ability to trigger biochemical signals from TCR complex because of
activation of ubiquitin ligases and proteolytic degradation of receptor-associated signaling
proteins; T cells that recognize self-antigens receive inhibitory signal from receptors structurally
homologous to CD28 but serve opposite functions
 Inhibitory receptors include CTLA-4 (binds B7 molecules) and PD-1 (binds 2 ligands
expressed on wide variety of cells); loss of either gene develops autoimmune disease
 Affects mature B cells in peripheral tissues; in absence of specific helper T cells, B cells unable to
respond to subsequent antigenic stimulation and may be excluded from lymphoid follicles
resulting in their death
o Suppression by Tregs – Tregs develop in thymus as result of recognition of self-antigens; may be induced
in peripheral lymphoid tissues
 CD4+ cells that constitutively express CD25, α chain of IL-2 receptor, and Foxp3
 IL-2 and Foxp3 required for development and maintenance of functional CD4+ Tregs
 Mutations in Foxp3 result in IPEX (systemic autoimmune; Immune dysregulation,
Polyendocrinopathy, Enteropathy, X-linked)
 Mutations in IL-2 results in multi-organ autoimmunity
 Polymorphisms in CD25 cause MS and other autoimmune diseases
o Deletion by activation-induced cell death: consequence of T-cell activation
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If T cells recognize self-antigens, they express pro-apoptotic Bim w/o anti-apoptotic Bcl-2 and
Bcl-x (induction requires full set of signals for lymphocyte activation
 Unopposed Bim triggers apoptosis by mitochondrial pathway
 Cells express Fas (CD95); FasL (membrane protein structurally homologous to TNF) expressed
mainly on activated T lymphocytes
 Engagement of Fas by FasL induces apoptosis of activated T cells by death receptor path
 Self-reactive B cells may be deleted by FasL on T cells engaging Fas on B cells
 Some antigens hidden (sequestered) from immune system (tissues where antigens located don’t
communicate w/blood and lymph); self-antigens don’t induce tolerance but fail to elicit immune
responses (testis, eye, brain); these sites immune-privileged sites
 If antigens from these tissues released due to trauma or infection, results in immune
response that leads to prolonged tissue inflammation and injury (post-traumatic orchitis
and uveitis)
 Most autoimmune diseases complex multigenic disorders (association w/MHC and HLA mutations)
o Polymorphisms in PTPN-22 (encodes tyrosine phosphatase associated w/RA, type 1 DM, etc.); most
frequently implicated gene in autoimmunity; mutations unable to control activity of tyrosine kinases
involved in lymphocyte responses
o Polymorphisms in NOD-2 associated w/Crohn disease (cytoplasmic sensor of microbes)
 Disease-associate variant ineffective at sensing intestinal microbes, resulting in entry of and
chronic inflammatory responses against commensal bacteria
o Genes encoding IL-2 receptor (CD25) and IL-7 receptor α chains associated w/MS and others
 Cytokines control maintenance of Tregs
o B cells express Fc receptor that recognizes IgG antibodies bound to antigens and switches off further
antibody production; knockout of receptor results in autoimmunity (B cells not controlled)
 Infections can upregulate expression of costimulators on APCs; if cells present self-antigens, results in
breakdown of anergy and activation of T cells specific for self-antigens
 Some microbes express antigens that have same amino acid sequences as self-antigens (molecular mimicry)
o Rheumatic heart disease: antibodies against strep cross-react w/myocardial proteins and cause
myocarditis
 Some viruses cause polyclonal B-cell activation, resulting in production of autoantibodies; tissue injury may
release self-antigens and structurally alter self-antigens so they are able to activate T cells not tolerant to new
modified antigens
o Infections induce production of cytokines that recruit lymphocytes (including self-reactive) to sites of
self-antigens
 Some infections protect against some autoimmune diseases; promote low-level IL-2 production (essential for
maintaining Tregs
 Once autoimmune disease induced, it is progressive, sometimes w/sporadic relapses and remissions
o Immune system contains many intrinsic amplification loops that allow small numbers of antigen-specific
lymphocytes to accomplish task of eradicating infections; when response inappropriately directed,
amplification mechanisms exacerbate injury
o Epitope spreading – infections damage tissues, release self-antigens, and expose epitopes of antigens
normally concealed from immune system; result is continuing activation of lymphocytes that recognize
previously hidden epitopes
 Clinical and pathological manifestations determined by nature of underlying immune response
o TH1 responses – destructive macrophage-rich inflammation and production of antibodies that cause
tissue damage by activating complement and binding Fc receptors
o TH17 responses underlie inflammatory lesions dominated by neutrophils as well as monocytes
 Autoimmune diseases show substantial clinical, pathologic, and serologic overlaps, so precise phenotypic
classification difficult
Systemic Lupus Erythematosus
 Vast array of autoantibodies, particularly ANAs
 Acute or insidious in onset; chronic remitting and relapsing, often febrile, illness characterized principally by
injury to skin, joints, kidney, and serosal membranes
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Antibodies recognize diverse nuclear and cytoplasmic components of cell; not organ or species specific
o Some directed against cell surface antigens of blood els
ANAs directed against nuclear antigens grouped into
o Antibodies to DNA
o Antibodies to histones
o Antibodies to nonhistone proteins bound to RNA
o Antibodies to nucleolar antigens
ANAs detected by indirect immunofluorescence; sensitive (positive in virtually every SLE patient) not specific
(pts w/other autoimmune diseases frequently positive)
o Homogeneous (diffuse) nuclear staining – antibodies to chromatin, histones, and occasionally ds DNA
o Rim (peripheral) staining – antibodies to ds DNA
o Speckled pattern – presence of uniform or variable-sized speckles; least specific (presence of antibodies
to non-DNA nuclear constituents)
o Nucleolar pattern – few discrete spots of fluorescence in nucleus and represents antibodies to RNA;
most often in patients w/systemic sclerosis
Generic ANAs – bind variety of nuclear antigens (DNA, RNA, and proteins)
Antibodies to ds DNA and Smith (Sm) antigen diagnostic SLE; don’t penetrate PM (only if cell damaged and
nucleus exposed)
Antiphospholipid antibodies present in 40-50% of lupus patients; directed against epitopes of plasma proteins
when in complex w/phospholipids
o Include prothrombin, annexin V, β2-glycoprotein I, protein S, and protein C
o Antibodies against phospholipid-β2-glycoprotein complex also bind cardiolipin antigen (used in syphilis
serology) and therefore, SLE patients may have false-positive syphilis test
 Can interfere w/clotting tests (PTT), so sometimes called lupus anticoagulant
o Have hypercoagulable state (venous and arterial thromboses associated w/miscarriages and focal
cerebral or ocular ischemia)
o Above = secondary antiphospholipid antibody syndrome
o Primary antiphospholipid syndrome – above without associated SLE
Fundamental defect in SLE is failure of mechanisms that maintain self-tolerance
Specific alleles of HLA-DQ locus linked to production of anti-ds DNA, anti-Sm, and antiphospholipid antibodies
Some SLE patients have inherited deficiencies of early complement components; lack of complement impairs
removal of circulating immune complexes by mononuclear phagocyte system, favoring tissue deposition
o Deficiency of C1q results in defective phagocytic clearance of apoptotic cells
Immunological factors
o Failure of self-tolerance in B cells
o CD4+ T cells specific for nucleosomal antigens contribute to production of autoantibodies
o Nuclear DNA and RNA contained in immune complexes may activate B lymphocytes by engaging TLRs
o Peripheral blood lymphocytes exposed to type I interferons (antiviral cytokines normally produced
during innate immune responses to viruses)
 Nucleic acids engage TLRs on DCs and stimulate production of interferons (self-nucleic acids
mimic microbial counterparts)
o BAFF – promotes survival of B cells; increased production in SLE patients
Exposure to UV light exacerbates disease in many individuals; irradiation induces apoptosis in cells and alters
DNA to become immunogenic
o Modulates immune response by stimulating keratinocytes to produce IL-1 (promotes inflammation)
Sex hormones – frequency 10x greater in women than men in 17-55 age group; exacerbation during menses and
pregnancy
Drugs such as hydralazine, procainamide, and D-penicillamine induce SLE-like response
Most visceral lesions caused by type III hypersensitivity
LE cell – any phagocytic leukocyte that has engulfed denatured nucleus of injured cell (LE bodies); sometimes
found in pericardial or pleural effusions in patients

Lupus nephritis – up to 50% of pts; immune complex deposition in glomeruli, tubular or peritubular capillary
BMs, or larger blood vessels
o Thrombi in glomerular capillaries, arterioles, or arteries; often associated w/antiphospholipid Ig’s
o Class I (minimal mesangial), class II (mesangial proliferative), class III (focal proliferative), class IV (diffuse
proliferative), and class V (membranous)
 Mesangial lupus glomerulonephritis: no or slight (class I) to moderate (class II) increase in both mesangial matrix
and number of mesangial cells
o Granular mesangial deposits of immunoglobulin and complement always present
 Focal proliferative glomerulonephritis (class III); lesions may be segmental (affecting only portion of glomerulus)
or global (involving entire glomerulus); glomeruli may exhibit crescent formation, fibrinoid necrosis, proliferation
of endothelial and mesangial cells, infiltrating leukocytes, and eosinophilic deposits or intracapillary thrombi
(correlate w/hematuria and proteinuria)
 Diffuse proliferative glomerulonephritis (class IV) most severe form; 35-60% of pts; proliferation of endothelial,
mesangial, and sometimes epithelial cells (producing cellular crescents that fill Bowman’s space)
o Hematuria and proteinuria; hypertension and mild to severe renal insufficiency common
 Membranous glomerulonephritis (class V) – diffuse thickening of capillary walls; 10-15% of pts; severe
proteinuria or nephrotic syndrome
 All classes show variable amounts of mesangial deposits (mainly subepithelial in membranous); subendothelial
(between endothelium and BM) in proliferative types (class III and IV)
o Deposits create homogeneous thickening of capillary wall (wire-loop in light microscopy)
 Characteristic erythema affects malar area (butterfly) in 50% of patients
o Urticaria, bullae, maculopapular lesions, and ulcerations occur
o Exposure to sunlight incites or accentuates
o Involved areas show vascuolar degeneration of basal layer of epidermis
o Edema and perivascular inflammation in dermis
o Vasculitis and fibrinoid necrosis may be prominent
o Deposition of immunoglobulin and complement along dermoepidermal junction (may be present in
uninvolved skin)
 Joint involvement – nonerosive synovitis w/little deformity
 Neuropsychiatric symptoms – noninflammatory occlusion of small vessels by intimal proliferation sometimes
noted; due to endothelial damage by antiphospholipid antibodies
 Pericardial involvement in up to 50% of patients
o Myocarditis (mononuclear cell infiltration) may cause resting tachycardia and electrocardiographic
abnormalities
o Valvular abnormalities primarily in mitral and aortic valves; diffuse leaflet thickening associated
w/dysfunction (Libman-Sacks endocarditis)
 Warty deposits on any heart valve on either surface of leaflets
o Can have coronary atherosclerosis (HTN, obesity, and hyperlipidemia more common in SLE pts)
 Immune complexes and antiphospholipid antibodies cause endothelial damage and promote
 Splenomegaly, capsular thickening, and follicular hyperplasia common features; central penicilliary arteries show
concentric intimal and smooth muscle cell hyperplasia (onion-skin lesions)
 Pleuritis and pleural effusions affect almost 50% of pts; sometimes chronic interstitial fibrosis and secondary
pulmonary HTN
 LE (hematoxylin) bodies in bone marrow or other organs strongly indicative of SLE
 Lymph nodes may be enlarged w/hyperplastic follicles or necrotizing lymphadenitis
 Prone to infections because of underlying immune dysfunction and treatment w/immunosuppressive drugs
 During acute flare-ups, increased formation of immune complexes and accompanying complement activation
result in hypocomplementemia
 Disease exacerbatins usually treated by corticosteroids or immunosuppressive drugs
 Most common causes of death are renal failure and intercurrent infections
Chronic Discoid Lupus Erythematosus
 Disease where skin manifestations mimic SLE, but systemic manifestations rare

Presence of skin plaques showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin
atrophy surrounded by elevated erythematous border
 Face and scalp usually affected
 Disease usually confined to skin (5-10% develop multisystem manifestations after many years)
 Antibodies to ds DNA rarely present
 Immunofluorescence of skin biopsy show deposition of immunoglobulin and C3 at dermoepidermal junction
Subacute Cutaneous Lupus Erythematosus
 Predominant skin involvement; skin rash tends to be widespread, superficial, and non-scarring
 Most have mild systemic Sx consistent w/SLE
 Strong association w/antibodies to SS-A antigen and HLA-DR3 genotype
 Group intermediate between SLE and lupus erythematosus localized only to skin
Drug-Induced Lupus Erythematosus
 Develops in pts receiving hydralazine, procainamide, isoniazid, and D-penicillamine
 Drugs produce ANAs, but most patients don’t have Sx
 Multiple organs affected, but renal and CNS don’t
 Extremely high frequency of antibodies for histone
 People w/HLA-DR4 allele at greater risk of developing after administration of hydralazine
 Disease remits after withdrawal of drug
Rheumatoid Arthritis
 Affects primarily joints but may involve extra-articular tissues (skin, blood vessels, lungs, and heart)
Sjögren Syndrome
 Chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting from
immunologically mediated destruction of lacrimal and salivary glands; infiltrate of activated CD4+ T cells and
some B cells (including plasma cells)
 Isolated disorder (sicca syndrome) or more often in association w/another autoimmune (secondary form)
 RA most common associated disorder
 75% of pts have rheumatoid factor (antibody reactive to IgG) whether or not coexisting RA
 ANAs detected in 50-80% of pts
 Antibodies directed against 2 ribonucleoprotein antigens: SS-A (Ro) and SS-B (La) detected in 90% of pts
o Pts w/high titers of SS-A antibodies more likely to have early disease onset, longer duration, and
extraglandular manifestations (cutaneous vasculitis and nephritis)
 Weak association w/HLA-B8, HLA-DR3, DRW52, HLA-DQA1, and HLA-DQB1 loci
o In pts w/anti-SS-A or anti-SS-B antibodies, specific alleles of HLA-DQA1 and HLA-DQB1 frequent
o Inheritance of certain class II molecules predisposes
 Initiating trigger may be viral infection of salivary glands (causes local cell death and release of tissue selfantigens); in genetically susceptible, CD4+ T cells and B cells specific for self-antigens may have escaped
tolerance and are able to react
 Viruses that serve as initiating stimuli include EBV and hepatitis C viruses
o Small proportion of individuals infected w/human T-cell lymphotropic virus type 1 develop identical Sx
 Any exocrine gland may be involved; just prefer lacrimal and salivary
o Periductal and perivascular lymphocytic infiltration  lymphoid follicles w/germinal centers found 
ductal lining epithelial cells may show hyperplasia, obstructing ducts  atrophy of acini, fibrosis, and
hyalinization  atrophy and replacement of parenchyma w/fat
 High risk for development of B cell lymphomas
 Corneal epithelium becomes inflamed, eroded, and ulcerated; oral mucosa atrophies w/inflammatory fissuring
and ulceration; dryness and crusting of nose leads to ulcerations and perforation of nasal septum
 Most commonly in older women (50-60)
 Thick secretions accumulate in conjunctival sac
 Extraglandular (1/3) synovitis, diffuse pulmonary fibrosis, and peripheral neuropathy
o More common in people w/high titers of anti-SS-A antibodies
o Glomerular lesions extremely rare (defects of tubular function (renal tubular acidosis, uricosuria, and
phosphaturia) often seen)

Mikulicz syndrome – combo of lacrimal and salivary gland inflammatory involvement from any cause
o Biopsy of lip to examine minor salivary glands essential for Dx of Sjögren syndrome
 Lymph nodes hyperplastic
 If reaction continues unabated, strong tendency for individual clones in population of B cells to gain growth
advantage; indicative of development of marginal zone lymphoma
Systemic Sclerosis (Scleroderma)
 Chronic disease characterized by
o Chronic inflammation from autoimmunity
o Widespread damage to small blood vessels
o Progressive interstitial and perivascular fibrosis in throughout body
 Skin most commonly affected, GI tract, kidneys, heart, muscles, and lungs frequently involved
 In most, disease progresses to visceral involvement w/death from renal failure, cardiac failure, pulmonary
insufficiency, or intestinal malabsorption
 Diffuse scleroderma (widespread skin involvement at onset w/rapid progression and early visceral involvement)
 Limited scleroderma (skin involvement confined to fingers, forearms, and face; late visceral invovlement)
o Some pts develop combo of calcinosis, Raynaud’s phenomenon (episodic vasoconstriction of arteries in
extremities), esophageal dysmotility, sclerodactylly, and telangiectasia (CREST) syndrome
 Autoimmune response, vascular damage, and collagen deposition contribute to ultimate tissue injury
 CD4+ T cells accumulate in skin and release cytokines that activate inflammatory cells and fibroblasts
o Secreted cytokines (TGF-β and IL-13) stimulate transcription of genes that encode collagen and ECM
proteins in fibroblasts
o Other cytokines recruit WBCs and propagate chronic inflammation
 Virtually all patients have ANAs that react w/variety of nuclear antigens
o Anti-Scl 70: directed against DNA topoisomerase I; 10-20% of pts; highly specific; more likely to have
pulmonary fibrosis and peripheral vascular disease
o Anticentromere antibody: 20-30% of pts; tend to have CREST syndrome or limited cutaneous form
 Microvascular damage early in course; intimal proliferation; capillary dilation w/leaking and destruction
o Nailfold capillary loops distorted early in course; disappear later
o Signs of increased endothelial activation and injury (vWF) and increased platelet activation (increase in
circulating platelet aggregates)
 Repeated cycles of endothelial injury followed by platelet aggregation lead to release of PDGF and TGF-β that
trigger perivascular fibrosis
o Vascular smooth muscle cells increase expression of adrenergic receptors
o Widespread narrowing of microvasculature leads to ischemic injury and scarring
 Progressive fibrosis from actions of fibrogenic cytokines produced by infiltrating WBCs, hyperresponsiveness of
fibroblasts to cytokines, and scarring following ischemic damage from vascular lesions
 Marfan syndrome – mutations in fibrillin-1 gene; some features of systemic sclerosis also seen
 Diffuse sclerotic atrophy of skin; begins in fingers and distal regions of UEs; extends proximaly
o Edema and perivascular infiltrates of CD4+ T cells w/swelling and degeneration of collagen fibers
(become eosinophilic)
o Capillaries and small arteries thicken basal lamina; endothelial cell damage; partial occlusion
o Increasing fibrosis of dermis, which becomes tightly bound to SQ structures; increase of compact
collagen in dermis w/thinning of epidermis, loss of rete pegs, atrophy of dermal appendages, and
hyaline thickening of walls of dermal arterioles and capillaries
o In advanced stages, fingers have tapered, claw-like appearance w/restriction of ROM; loss of blood
supply leads to cutaneous ulceration and atrophic changes in terminal phalanges (can amputate)
 Alimentary tract affected in 90% of patients; progressive atrophy and collagenous fibrous replacement of
muscularis (most severe in esophagus); lower 2/3 of esophagus develops rubber-hose inflexibility
o Dysfunction of lower esophageal sphincter gives rise to GERD
o Mucosa thinned and may ulcerate; excessive collagenization of lamina propria and submucosa
o Loss of villi and microvilli in small bowel cause malabsorption syndrome
 Inflammation of synovium w/hypertrophy and hyperplasia of synovial soft tissues early stage; fibrosis later
o Joint destruction not common
o Inflammatory myositis (similar to polymyositis) may develop in 10% of pts
 Renal abnormalities in 2/3 of patients w/systemic sclerosis; vascular lesions most prominent
o Interlobular arteries show intimal thickening as result of deposition of mucinous or finely collagenous
material (stains for glycoprotein and acid mucopolysaccharides)
o Concentric proliferation of intimal cells; restricted to smaller vessels and not always associated w/HTN
o HTN occurs in 30% of pts; 20% have malignant HTN
 Vascular alterations more pronounced; associated w/fibrinoid necrosis involving arterioles
w/thrombosis and infarction
 Often die of renal failure
o Proteinuria – rarely severe enough to cause nephrotic syndrome
 Lungs involved in more than 50% of pts; pulmonary HTN and interstitial fibrosis
o Pulmonary vasospasm (secondary to pulmonary vascular endothelial dysfunction) important in HTN
 Pericarditis w/effusion and myocardial fibrosis w/thickening of intramyocardial arterioles; 1/3 of pts
o Clinical myocardial involvement less common
o Myocardial fibrosis may cause either arrhythmias or cardiac failure
 Raynaud’s phenomenon in virtually all patients
 Destruction of esophageal wall leads to atony and dilation, esp. in lower end
Inflammatory Myopathies
 Group of disorders characterized by injury and inflammation of mainly skeletal muscles
 Dermatomyositis, polymyositis, and inclusion-body myositis comprise this group; may occur alone or in combo
(esp. w/systemic sclerosis)
Mixed Connective Tissue Disease
 Clinical features mixture of features of SLE, systemic sclerosis, and polymyositis
 Characterized by serologically high titers of antibodies to ribonucleoprotein particle-containing U1
ribonucleoprotein
 Modest renal involvement, but good response to corticosteroids
 Can evolve into classicl SLE or systemic sclerosis
 Complications include pulmonary HTN and renal disease resembling systemic sclerosis
Polyarteritis Nodosa and Other Vasculitides
 Necrotizing inflammation of walls of blood vessels of immunological pathogenesis
 Noninfectious vasculitis – not due to direct infection of blood vessel wall (as occurs in wall of abscess); any type
of vessel involved