Diseases of the Immune System Ch. 4 p (99 – 159) Feb. 28 /2016 March 6 /2016

MHC Collection of genes on chromosome 6 Three regions: class I, class II, class III Highly polymorphic! Gene products: class I molecules class II molecules class III molecules (and other stuff) Major histocompatibility (MHC) complex

MHC MOLECULES (Gene Products) MHC I; (All nucleated cells and platelets) MHC II; (APC’s, i.e., macs and dendritics, lymphs), MHC III; Complement System Proteins

class I MHC moleculeclass II MHC molecule class II MHC genesclass I MHC genesclass III MHC genes

MHC I MHC II

IMMUNE SYSTEM DISORDERS HYPERSENSITIVITY REACTIONS “AUTO”-IMMUNE DISEASES IMMUNE DEFICIENCY : –PRIMARY (GENETIC) –SECONDARY (ACQUIRED)

HYPERSENSITIVITY REACTIONS “HR” Type I (Immediate HR) Type II (Ab Mediated HR) Type III (Immune- Complex Mediated HR) Type IV (Cell- Mediated HR)

Type I hypersensitivity (Immediate HR)

Type I hypersensitivity  There are two forms of anaphylaxis: Systemic anaphylaxis: acute asthma, laryngeal edema, diarrhea, urticaria, and shock. e.g penicillin allergy and bee sting allergy. Local anaphylaxis (atopy): in10% of people hay fever, hives, asthma, etc. e.g food allergies and hay fever to pollen.

Type I hypersensitivity; Beneath the nasal mucosa at the left, eosinophils, plasma cells & lymphocytes

The acute laryngeal edema due to an anaphylactic reaction to penicillin

Variables that probably contribute to the strong TH2 responses to allergens include the route of entry, dose, and chronicity of antigen exposure, and the genetic makeup of the host

TYPE II HR ANTIBODY MEDIATED IMMUNITY  Abs (IgG, IgM), attach to cell surfaces Opsonization, Phagocytosis Complement fixation, (cascade of C1q, C1r, C1s, C2, C3, C4, C5….. ), LYSIS of the cell membrane. Anti cell membrane receptors  The Ags may be normal molecules intrinsic to cell membranes or in the ECM, or they may be adsorbed exogenous antigens (e.g., a drug metabolite)

Type II HR: Opsonization & Phagocytosis

Type II HR Inflammation:

Type II Hypersensitivity Transfusion reactions: incompatible RBC's or serum is transfused. Autoimmune hemolytic anemia: antibody is made against one's own RBC's. Erythroblastosis fetalis: maternal IgG crosses the placenta and attaches to fetal RBC's. Goodpasture's syndrome: glomerular basement membrane antibody is present.

Idiopathic Autoimmune hemolytic anemia

This is the linear pattern of immunofluorescence with Ab to IgG in a patient with Goodpasture syndrome. The even linear pattern is produced because the Ab is directed against the entire glomerular BM (antiglomerular BM Ab). Goodpasture syndrome

Type II HR; Ab-mediated cellular dysfunction (Antireceptor Abs) Graves disease Myasthenia gravis

Graves Disease Myasthenia gravis

TYPE III HYPERSENSITIVITY IMMUNE COMPLEX MEDIATED Ag/Ab“Complexes” Where do they go? ( high hemodynamic Pr + Filtration function) –Kidney (Glomerular BM),,,,,Pr Urea –Blood Vessels,,,,,,, Peticheal hge –Skin,,,,,,, Urticaria –Joints,,,,,, arthralgia –LN –Tissue damages,

Type III HR The Ags; Exogenous, microbial pr, as in post strep.GN Or Endogenous,, nucleoproteins as in SLE The Abs; IgG, IgM + Complement Tissue damage: Ac inflammation, acute necrotizing vasculitis, Microthrombi & iscemic necrosis

TYPE III HR,,,, Inflammatory Reaction Platelet aggregation & activate Hageman factor activate Hageman factor Microthrombi Ischemic necrosis Tissue damage: Ac inflammation, acute necrotizing vasculitis vasculitis, GN, arthritis, Petechial skin hges The immune complexes activate; 1 2  Consumption of complement may result in decreased serum complement levels. Pg, vasodilator, chemotactic, lysosomal enz digesting BM, collagen, elastin, & cartilage, ROS

Arthus reaction Serum sickness

Immune Complex-Mediated Vascular Inflammation (Vasculitis, ?HBV Ags)

Fibrinoid necrosis in Ar in polyarteritis nodosa. The wall of the artery shows a circumferential bright pink area of necrosis with protein deposition (Imm Complexes & inflammation ? Reversible Lupus nephritis; Deposition of IgG, detected by immunofluorescence Chronic Unknown Ag Arthus reaction, an area of tissue necrosis appears as a result of acute immune complex vasculitis

TYPE IV HYPERSENSITIVITY CELL-MEDIATED (T-CELL) DELAYED HYPERSENSITIVITY Direct antigen  Cell contact Granuloma formation Contact dermatitis Tuberculin Skin Reaction

Mechanisms of T cell–mediated (type IV) HR (1)cytokine-mediated inflammation, by CD4+ T cells, & (2)Direct cell cytotoxicity, mediated by CD8+ T cells TH1 TH17 If the DCs produce IL-12, the naive T cells differentiate into TH1 type If the APCs produce IL-1, IL-6, or IL-23 instead of IL-12, the CD4+ cells develop into TH17

 Cytokine-mediated inflammation: CD4+ T,,,,,,,TH1 and TH17 effector cells. Subsequent exposure to the Ag results in the secretion of cytokines. IFN-γ activates MQ,,,,,secrete cytokines IL-17 & other cytokines recruit WBC,,,,,Inflammation  T cell–mediated cytotoxicity: CD8+ CD8+ T cells also secrete IFN-γ.

T cell–mediated cytotoxicity: CD8+ -Contact dermatitis -Graft rejection -GVH

ACUTE CELLULAR (T)ACUTE HUMORAL CHRONIC

Tuberculin Test  Cytokine-mediated inflammation: CD4+ T,,,,,,,TH1 and TH17 effector cells

Sequence of events in the natural history of primary pulmonary tuberculosis

RENAL TRANSPLANT REJECTION HYPERACUTEHYPERACUTE (minutes) : AG/AB reaction of vascular endothelium ACUTEACUTE (days  months): cellular (INTERSTITIAL infiltrate) and humoral (VASCULITIS) CHRONICCHRONIC (months): slow vascular fibrosis

 IgE IgE  Atopy Atopy  Anaphylaxis Anaphylaxis  Asthma Asthma AllergyAllergy (immediate) I  IgM or IgG IgMIgG  (Complem ent)Complem ent  Autoimmune hemolytic anemia Autoimmune hemolytic anemia  Thrombocytopenia Thrombocytopenia  Erythroblastosis fetalis Erythroblastosis fetalis  Goodpasture's syndrome Goodpasture's syndrome Cytotoxic, antibody-dependent II  IgG IgG  (Complem ent)Complem ent  Serum sickness Serum sickness  Arthus reaction Arthus reaction  (SLE)SLE Immune complexImmune complex disease III  T-cells T-cells Contact dermatitis  TB, Mantoux testMantoux test  Chronic transplant rejection Chronic transplant rejection  Multiple sclerosis [3] Multiple sclerosis[3] Delayed-type HR (DTH), cell-mediated immune memory response,cell-mediated immune memory response antibody-independent IV  IgM or IgG IgMIgG  (Complem ent)Complem ent  Grave's disease Grave's disease  Myasthenia Gravis Myasthenia Gravis AutoimmuneAutoimmune disease, receptor mediated V