I.

II.

Lymphoid Structures a. LN i. Secondary lymphoid organ w/many afferents, 1 or more efferents ii. Encapsulated w/trabeculae iii. Fns nonspecific filtration by macrophages, storage & activation of B & T cells, Ab production iv. Follicle 1. Site of B-cell localization & proliferation 2. In outer cortex 3. Primary follicles are dense & dormant 4. Secondary follicles have pale central germinal centers & are active v. Medulla 1. Medullary cords closely packed lymphocytes & plasma cells 2. Medullary sinuses communicate w/efferent lymphatics; contain reticular cells & macrophages vi. Paracortex 1. T cells 2. Region of cortex btwn follicles & medulla 3. Contains high endothelial venules through which T & B cells enter from blood 4. In extreme cellular immune response (i.e. viral), becomes greatly enlarged 5. Not well developed in pts w/DiGeorge syndrome b. Lymph drainage i. Upper limb, lateral breast axillary ii. Stomach celiac iii. Duodenum, jejunum superior mesenteric iv. Sigmoid colon colic inferior mesenteric v. Rectum, lower portion of anal canal (ABOVE pectinate line) internal iliac vi. Anal canal (BELOW pectinate line), scrotum, superficial thigh superficial inguinal vii. Testes superficial & deep plexuses para-aortic viii. Lateral side of dorsum of foot popliteal ix. R arm, chest & of head R lymphatic duct (thoracic duct does everything else) c. Sinusoids of spleen i. Long vascular channels in red pulp w/fenestrated barrel hoop BM ii. Macrophages are nearby remove encapsulated bacteria iii. T cells peri-arterial lymphatic sheath w/in white pulp of spleen iv. B cells follicles w/in white pulp of spleen v. Splenic dysfn: decreased IgM decreased complement activation decreased C3b opsonization (liver makes complement) increased susceptibility to encapsulated bugs (cant clear bacteria) 1. Strep pneumo, Hib, N. men, Salmonella, Klebsiella, GBS vi. Post-splenectomy Howell-Jolly bodies (nuclear remnants), target cells, thrombocytosis vii. Fn of spleen site of Ab synthesis & reservoir of phagocytic cells that can remove circulating pathogens d. Thymus i. Site of T-cell differentiation & maturation ii. Encapsulated rd iii. From epithelium of 3 branchial pouches iv. Lymphocytes of mesenchymal origin v. Cortex dense w/immature T cells; + selection here (MHC restriction) vi. Medulla pale w/mature T cells & epithelial reticular cells containing Hassalls corpuscles; selection here (non-reactive to self) Lymphocytes a. Innate immunity vs adaptive immunity

Innate Receptors are germline-encoded

Response is fast & non-specific No memory PMNs, macrophages, DCs, NK cells (lymphoid origin), complement b. MHC I i. Encoded by HLA-A, HLA-B, HLA-C ii. Binds TCR & CD8 iii. Expressed on all nucleated cells but NOT on RBCs iv. Ag is loaded in RER w/mostly IC peptides v. Mediates viral immunity vi. Pairs w/B2-microglobulin (aids in transport to cell surface) c. MHC II i. Encoded by HLA-DR, HLA-DP, HLA-DQ ii. Binds TCR & CD4 iii. Expressed only on APCs iv. Ag is loaded following release of invariant chain in an acidifed endosome d. HLA subtypes assoc. w/disease i. A3 hemochromatosis ii. B27 psoriasis, ankylosing spondylitis, inflamm bowel disease, Reiters syndrome iii. DQ2/DQ8 celiac disease iv. DR2 MS, hay fever, SLE, Goodpastures v. DR3 DM type 1, Graves disease vi. DR4 DM type 1, RA vii. DR5 pernicious anemia (B12 def), Hashimotos thyroiditis e. NK cells i. Use perforin & granzyme to induce apoptosis of virally infected cells & tumor cells ii. Only lymphocyte member of innate immune system iii. Activity enhanced by IL-2, 12; IFN-a, B iv. Induced to kill when exposed to nonspecific activation signal on target cell and/or to an absence of class I MHC on target cell surface f. B cell fns i. Make Ab 1. Opsonize bacteria, neutralize viruses IgG 2. Activate complement IgM, IgG 3. Sensitize mast cells IgE ii. Allergy (type I HSR) IgE iii. Cytotoxic (type II) & IC (type III) HSR IgG iv. Hyperacute & humorally-mediatd acute & chronic organ rejection g. T cell fns i. CD4 help B cells make Ab & produce cytokines to activate other cells of immune system ii. CD8 kill virus-infected cells directly iii. Delayed cell-mediated HSR (type IV) iv. Acute & chronic cellular organ rejection h. Differentiation of T cells i. BM T-cell precursor ii. Thymus 1. Cortex (+ selection) CD4+CD8+ T cells expressing TCRs capable of binding surface self-MHC molecules survive

Adaptive Receptors undergo V(D)J recombination during lymphocyte development st Response is slow on 1 exposure Memory response is faster & more robust T cells, B cells, circulating Ab

2. iii. LN

Medulla (- selection) CD4+ or CD8+ T cells expressing TCRs w/high affinity for self Ags undergo apoptosis

i.

j.

1. CD8 cytotoxic T cell kills virus-infected, neoplastic & donor graft cells 2. CD4 helper T cell IL-12 Th1 cell OR IL-4 Th2 cell T & B cell activation i. APCs DCs (only one that can activate nave T-cell), macrophages, B-cells ii. 2 signals are need for activation & class switching iii. Nave T-cell activation 1. Foreign body is phagocytosd by DC 2. Foreign Ag is presented on MHC II & recognized by TCR on Th cell; Ag is presented on MHC I to Tc cells (SIGNAL 1) 3. Costimulatory signal is given by interaction of B7 (DC) & CD28 (nave T cell) (SIGNAL 2) 4. Th cell activates & produces cytokines; Tc cell activates & recognizes and kills virusinfected cell iv. B-cell activation & class switching 1. Helper T cell is activated 2. B cell receptor-mediated endocytosis; foreign Ag is presented on MHC II & is recognized by TCR on Th cell (SIGNAL 1) 3. CD40R on B cell binds CD40 ligand on Th cell (SIGNAL 2) 4. Th cell secretes cytokines that determine Ig class switching of B-cell; B-cell activates & undergoes class switching, affinity maturation & Ab production Th1 vs Th2 cells Th1 Secretes IFN-y Activates macrophages

Th2 Secretes IL-4, 5, 10, 13 Recruits eosinophils for parasite defense; promotes IgE production by B cells Inhibited by IL-4, 10 (from Th2) Inhibited by IFN-y (from Th1) i. Macrophage-lymphocyte interaction activated lymphocytes (release IFN-y) & macrophages (release IL-1, TNF-a) stimulate one another ii. Th cells have CD4 binds to MHC II on APCs k. Cytotoxic T cells i. Kill virus-infected, neoplastic & donor graft cells by inducing apoptosis ii. Release cytotoxic granules containing preformed proteins 1. Perforin helps deliver content of granules into target cell 2. Granzyme serine protease that activates apoptosis inside target cell 3. Granulysin antimicrobial that induces apoptosis l. Regulatory T cells i. Help maintain specific immune tolerance by suppressing CD4 & CD8 T-cell effector fns ii. Express CD3, CD4, CD25 (alpha chain of IL-2R) cell surface markers iii. Activated Treg cells produce anti-inflamm cytokines IL-10, TGF-B m. Ab structure & fn i. Variable part of L & H chains recognizes Ags ii. Fc portion of IgM & IgG fixes complement iii. Heavy chain contributes to Fc & Fab fractions iv. Light chain contributes ONLY to Fab fraction v. Fab 1. Ag-binding fragment 2. Determines idiotype unique Ag-binding pocket; only 1 Agic specificity expressed per B cell vi. Fc

n.

o.

p.

1. Constant, carboxy terminal 2. Complement binding (IgG + IgM only), carb side chains 3. Determines isotype (IgM, IgD, etc) Ab diversity is generated by i. Random recombination of VJ (light-chain) or V(D)J (heavy-chain) genes ii. Random combination of heavy chains w/light chains iii. Somatic hypermutation (after Ag stimulation) iv. Addition of nucleotides to DNA during recombination by TdT (terminal deoxynucleotidyl transferase) Ig isotypes i. Mature B lymphocytes express IgM & IgD on their surfaces ii. May differentiate by isotype switching (gene rearrangement, mediated by cytokines & CD40L) into plasma cells that secrete IgA, IgE or IgG iii. IgG 1. Main Ab in secondary (delayed) response to Ag 2. Most abundant isotype 3. Fixes complement, crosses placenta (passive immunity), opsonizes bacteria, neutralizes bacterial toxins & viruses 4. O type iv. IgA 1. Prevents attachment of bacteria & viruses to mucous membranes 2. Does not fix complement 3. Monomer (in circulation) or dimer (when secreted) 4. Crosses epithelial cells by transcytosis 5. Found in secretions (tears, saliva, mucus) & early breast milk (colostrum) 6. Picks up secretory component from epithelial cells before secretion v. IgM 1. Produced in primary (immediate) response to Ag 2. Fixes complement but does not cross placenta 3. Ag receptor on surface of B cells 4. Monomer on B cell or pentamer 5. Shape of pentamer allows it to efficiently trap free Ags out of tissue while humoral response evolves 6. A type, B type vi. IgD on surface of many B cells & in serum vii. IgE 1. Binds mast cells & basophils 2. Cross-links when exposed to allergen 3. Mediates immediate (type 1) HSR through release of inflamm mediators like histamine 4. Mediates immunity worms by activating eosinophils 5. Lowest concentration in serum Ag type & memory i. Thymus-independent 1. Ags lack peptide component cant be presented by MHC to T cells 2. Stimulate release of Abs & do not result in immunologic memory 3. Ex: LPS from cell envelope of gram bacteria; polysaccharide capsular Ag ii. Thymus-dependent 1. Ags containing protein component 2. Class switching & immunologic memory occur due to direct contact of B cells w/Th cells (CD40-CD40L interaction) 3. Ex: diphtheria vaccine

III.

Immune Responses a. Complement i. Alternative: spontaneous & microbial surfaces ii. Lectin: microbial surfaces, i.e. mannose iii. Classic: Ag-Ab complexes (IgG or IgM-mediated) iv. C3b opsonization v. C3a, C5a anaphylaxis vi. C5a neutrophil chemotaxis vii. C5b-9 cytolysis by MAC viii. C3b & IgG are the 2 primary opsonins in bacterial defense; C3b also helps clear IC ix. DAF & C1 esterase inhibitor help prevent complement activation on self cells (i.e. RBCs) x. Disorders 1. C1 esterase inhibitor def hereditary angioedema; ACEIs are C/I 2. C3 def severe recurrent pyogenic sinus & resp tract infections; increased susceptibility to type III HSR 3. C5-9 def recurrent Neisseria bacteremia 4. DAF (GPI anchored enzyme) def complement-mediatd lysis of RBCs & PNH b. Important cytokines i. Secreted by macrophages 1. IL-1 endogenous pyrogen fever, acute inflamm; activates endothelium to express adhesion molecules; induces chemokine secretion to recruit leukocytes 2. IL-6 (also secreted by Th2 cells) endogenous pyrogen fever, stimulates production of acute-phase proteins 3. IL-8 major chemotactic factor for PMNs, induces phagocytosis of PMNs 4. IL-12 (also secreted by B cells) induces differentiation of T cells into Th1 cells, activates NK cells 5. TNF-a mediates septic shock, activates endothelium, causes leukocyte recruitment, vascular leak ii. Secreted by all T cells 1. IL-2 stimulates growth of Th, Tc, Treg cells 2. IL-3 supports growth & differentiation of BM stem cells, fns like GM-CSF iii. From Th1 cells 1. IFN-y activates macrophages & Th1 cells, suppresses Th2 cells, has antiviral & antitumor properties iv. From Th2 cells 1. IL-4 induces differentiation into Th2 cells, promotes growth of B cells, enhances class switching to IgE & IgG 2. IL-5 promotes differentiation of B cells, enhances class switching to IgA, stimulates growth & differentiation of eosinophils 3. IL-10 (also secreted by Treg cells) modulates inflamm response, inhibits actions of activated T cells & Th1; TGF-B has similar actions v. IFN mech 1. These are proteins that place uninfected cells in an antiviral stat 2. Induce production of ribonuclease that inhibits viral protin synthesis by degrading viral mRNA but not host mRNA 3. Alpha & beta inhibit viral protein synthesis 4. Gamma increases MHC I & II expression & Ag presentation in all cells 5. Activate NK cells to kill virus-infected cells c. Cell-surface proteins all cells except mature RBCs have MHC I i. T cells TCR (binds Ag-MHC complex), CD3 (assoc. w/TCR for signal transduction), CD28 (binds B7 on APC)

d. e.

f.

g.

ii. Th cells CD4, CD40L iii. Tc cells CD8 iv. B cells Ig (binds Ag), CD19, CD20, CD21 (EBVR), CD40, MHC II, B7 v. Macrophages CD14, CD40, MHC II, B7, Fc & C3bR (enhanced phagocytosis) vi. NK cells CD16 (binds Fc of IgG), CD56 (unique marker for NK) Anergy self-reactive T cells become non-reactive w/out costimulatory molecule; B cells also become anergic but tolerance is less complete than in T cells Effects of bacterial toxins i. SuperAgs (S. pyogenes & S. aureus) cross-link beta region of TCR to MHC II on APCs; can activate any T-cell massive release of cytokines ii. Endotoxins/LPS (gram bacteria) directly stimulate macrophages by binding to endotoxin receptor CD14; Th cells not involved Ag variation i. Bacteria Salmonella (2 flagellar variants), Borrelia (relapsing fever), Neisseria gonorrhoeae (pilus protein) ii. Virus influenza (major = shift; minor = drift) iii. Parasites trypanosomes (programmed rearrangement) iv. Some mechs for variation include DNA rearrangement & RNA segment reassortment (i.e. influenza major shift) Passive vs active immunity

Passive Active Via preformed Abs Via exposure to foreign Ags Rapid onset Slow onset Short span of Abs Long-lasting protection (memory) IgA in breastmilk, antitoxin, humanized mAb Natural infection, vaccines, toxoid If exposed to tetanus toxin, botulinum toxin, HBV or Combined passive & active immunizations can be given ravies virus, pts given preformed Abs in case of hep B or rabies exposure h. Vaccination i. Used to induce active immune response (humoral and/or cellular) to specific pathogens ii. Live attenuated 1. Bug loses pathogenicity but retains capacity for transient growth w/in inoculated host induces cellular response 2. Pro induces strong, often life-long immunity 3. Con may revert to virulent form 4. Ex: MMR, polio (Sabin), varicella, yellow fever, BCG iii. Inactivated or killed 1. Bug is inactivated by heat or chemicals, maintaining epitope structure on surface Ags is important for immune response induces humoral immunity 2. Pro stable & safer than live 3. Con weaker immune response, booster shots usually required 4. Ex: cholera, hep A, polio (Salk), rabies, flu, HBV iv. Acellular pertussis vaccine purified components of B. pertussis & detoxified pertussis toxin (toxoid) v. Tetanus vaccine tetanus toxoid (inactivatd form of tetanus toxin) vi. Hib vaccine bacterial capsular polysaccharide conjugated w/diphtheria toxoid i. HSR i. Type I 1. Anaphylactic & atopic 2. Free Ag cross-links IgE on pre-sensitized mast cells & basophils triggers release of vasoactive amines that act at postcapillary venules (i.e. histamine) 3. Rxn develops rapidly after Ag exposure b/c of preformed Ab

j.

4. Test skin test for specific IgE 5. Ex: anaphylaxis, allergic & atopic disorders (rhinitis, hay fever, eczema, hives, asthma) ii. Type II (disease tends to be specific to tissue or site where Ag is found) 1. Cytotoxic (Ab-mediated) IgM, IgG bind to fixed Ag on enemy cell cellular destruction 2. 3 mechs a. Opsonization phagocytosis or complement activation b. Complement-mediated lysis c. ADCC usualy due to NK cells 3. Test direct & indirect Coombs 4. Ex: AIHA, pernicious anemia, ITP, erythroblastosis fetalis, acute hemolytic transfusion rxns, rheumatic fever, Goodpastures, bullous pemphigoid, pemphigus vulgaris iii. Type III (can be assoc. w/vasculitis & systemic manifestations) 1. IC Ag-Ab (IgG) complexes activate complement attracts PMNs releases lysosomal enzymes 2. Test IF staining 3. Serum sickness a. IC disease (type III) where Abs to foreign proteins are made (5 days) b. IC form & deposit in membranes where they fix complement tissue damage vasculitis c. MC than Arthus rxn d. Mostly due to drugs (sulfonamides), not serum, acting as haptens e. Sx fever, urticaria, arthralgias, proteinuria, lymphadenopathy, low serum C3 (hypocomplementemia) 5-10 days after intravascular Ag exposure 4. Arthus rxn a. Local subacute Ab-mediatd HSR (type III) rxn b. Intradermal injection of Ag induces Abs form Ag-Ab complexes in skin c. Characterized by edema, necrosis & activation of complement 5. Ex: SLE, PAN, PSGN, serum sickness, Arthus rxn (i.e. swlling & inflamm after tetanus vaccine) iv. Type IV 1. Delayed (T-cell mediated) typ sensitized T cells encounter Ag release lymphokines macrophage activation (NO Ab INVOLVED) 2. Cell-mediated so not transferable by serum 3. Seen in transplant rejections, TB skin tests, touching (contact dermatitis) 4. Test patch test, PPD 5. Ex: MS, Guillain-Barre syndrome, PPD, contact dermatitis Blood transfusion rxns i. Allergic rxn 1. Type I HSR against plasma proteins in transfused blood 2. Sx urticaria, pruritus, wheezing, fever 3. Tx antihistamines ii. Anaphylactic rxn 1. Severe rxn 2. IgA-def individuals must receive blood products that lack IgA 3. Sx dyspnea, bronchospasm, hypotension, resp arrest, shock iii. Febrile non-hemolytic transfusion rxn 1. Type II HSR host Abs against donor HLA Ags & leukocytes 2. Sx fever, headache, chills, flushing iv. Acute hemolytic transfusion rxn

1. 2. k.

Type II HSR intravascular hemolysis (ABO blood group incompatibility) or extravascular hemolysis (host Ab rxn against foreign Ag on donor RBCs) Sx fever, hypotension, tachypnea, tachycardia, flank pain, Hbemia (intravascular), jaundice (extravascular)

l.

AutoAbs i. ANA SLE (non-specific) ii. Anti-dsDNA, anti-Smith SLE iii. Anti-histone drug-induced lupus iv. Rheumatoid factor, anti-CCP RA v. Anti-centromere scleroderma (CREST syndrome) vi. Anti-Scl-70 (anti-DNA topoisomerase I) scleroderma (diffuse) vii. Anti-mitochondrial primary biliary cirrhosis viii. IgA anti-endomysial, IgA anti-tissue transglutaminase celiac disease ix. Anti-basement membrane Goodpastures syndrome x. Anti-desmoglein pemphigus vulgaris xi. Anti-microsomal, anti-thyroglobulin Hashimotos thyroiditis xii. Anti-Jo-1, anti-SRP, anti-Mi-2 polymyositis, dermatomyositis xiii. Anti-SSA (anti-Ro), anti-SSB (anti-La) Sjogrens syndrome xiv. Anti-U1 RNP (ribonucleoprotein) mixed CT disease xv. Anti-smooth muscle autoimmune hepatitis xvi. Anti-glutamate decarboxylase DM type 1 xvii. c-ANCA (PR3-ANCA) granulomatosis w/polyangiitis (Wegeners) xviii. p-ANCA (MPO-ANCA) microscopic polyangiitis, Churg-Strauss syndrome Infections in immunodeficiency Pathogen Bacteria No T cells Sepsis No B cells Encapsulated (S. pneumo, Hib, N. men, Salmonella, Klebsiella, GBS) Enteroviral encephalitis, poliovirus (live vaccine C/I) GI giardiasis (no IgA) No Granulocytes Staph, Burkholderia cepacia, Serratia, Nocardia N/A No Complement Neisseria (no MAC)

Viruses

CMV, EBV, VZV, chronic infection w/resp/GI viruses Candida, PCP

Fungi/parasites m. B-cell disorders Disease X-linked (Brutons) agammaglobulinemia Selective IgA deficiency Common variable immunodeficiency (CVID)

Candida, Aspergillus

N/A

Defect

Presentation

Findings