Immunopathology Path 6266 Jan 22, 2014 Judy Aronson, M.D.

Objectives Define hypersensitivity List and explain 4 hypersensitivity mechanisms, with examples from human disease –Relate hypersensitivity mechanisms to SLE, an autoimmune disease Recognize basic features of normal renal histology –Describe histopathologic abnormalities that may be seen in SLE patients and correlate with general effects on renal function Through analysis of a recent journal article, explore and discuss some potential molecular mechanisms associated with renal immunopathology in SLE

Outline How does the immune response damage tissues? –Hypersensitivity mechanisms –Examples of immunopathologic disease –Autoimmune diseases Review renal histology and histopathology of lupus nephritis

The double edged sword of immune responses “Immunitas”: Freedom from disease Protective responses against infectious agents “Pathos”: Suffering/ disease Host tissue damage by immune response

Hypersensitivity reactions Mechanisms of immune-mediated injury Classified into 4 types (I-IV) Imperfect correlation between hypersensitivity reaction and disease syndrome –In some diseases, all 4 types may contribute –Humoral and cell-mediated mechanisms may co- exist

Categories of diseases with immunopathologic components Infectious Allergic Transplant rejection Graft vs. host disease Autoimmune

Hypersensitivity Reactions Type I: anaphylactic –allergy, asthma Type II: antibody-mediated –transfusion reaction Type III: immune complex-mediated –post-strep glomerulonephritis Type IV: cell-mediated, delayed type –tuberculosis

Adaptive immune responses Abbas, Cellular and Molecular Immunology, 5 th ed. Types I-IIIType IV

Type I hypersensitivity Immunoglobulin E (IgE) –made by plasma cells, specific for allergen Mast cells, basophils –Have receptors for Fc portion of IgE molecule –When antigen binds IgE variable regions, degranulation of cells occurs –Histamine and other vasoactive substances are released Severe reactions can be life-threatening!

Type I hypersensitivity

Mast cell mediators Primary mediators –Histamine: vasodilation and increased permeability, bronchoconstriction, mucus secretion –Tryptase: generate kinins, activate complement –Eosinophil chemotactic factor –Neutrophil chemotactic factor Secondary mediators –Lipid mediators (result from PLA2 activation) PAF LTC4, LTD4: vaso- dilation, bronchospasm LTB4: chemotactic factor PGD2: increased mucus, bronchospasm –Cytokines: TNF, IL-1, IL- 4, IL-5, IL-6)

Clinical diseases Systemic anaphylaxis –Urticaria (hives), bronchoconstriction, laryngeal edema, hypersecretion of mucus, vomiting, abdominal cramps –Life threatening Localized reactions—eg urticaria, hay fever Asthma

Urticaria (hives)

Asthma

Type II hypersensitivity Involves IgG or IgM antibodies that react with fixed antigen on cells or tissue components Mechanisms of damage: –cell lysis (complement, MAC) –inflammation (complement activation) –block normal cell function –stimulate excessive cell function

Complement A system of about 20 serum proteins Activation is by a proteolytic cascade mechanism –Classical pathway: initiated by Ag-Ab complexes –Alternative pathway: initiated by microbial surface –Lectin pathway Important products are formed at activating cell surface (opsonins, MAC) and in aqueous environment (anaphylatoxins)

Overview of complement activation pathways From: Robbins

Complement: Effector functions Formation of membrane attack complex, lysis of target cell Generation of C3a and C5a “anaphylatoxins” –Chemotactic factors for phagocytes, esp. pmn –Leukocyte activation –Mast cell degranulation –Bronchoconstriction Opsonization—coating surface of target cell with C fragments (esp. C3), promoting phagocytosis

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 2 January :24 PM) © 2005 Elsevier Activation and effector functions of complement

The Lytic Pathway of Complement From: Roitt

Biological Effects of C5a From: Roitt

Opsonization and phagocytosis From: Roitt

Type II Hypersensitivity

ABO antigens and transfusion

Type III hypersensitivity Caused by immune complexes (antigen- antibody) that are soluble and formed in antigen excess Circulating immune complexes deposited according to size, charge, local hemodynamics, etc. (e.g. glomeruli of kidney, joints, skin, small vessels) Complement is activated, inflammation ensues

Type III (Immune complex) Hypersensitivity

Type IV hypersensitivity T lymphocytes and macrophages are effector cells (cell-mediated immune reactions) –CD4 T cell immuniological inflammation and macrophage activation –CD8 T cell killing of targets

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 14 July :39 PM) © 2005 Elsevier Type IV hypersensitivity reactions

Functional CD4 subsets

Autoimmunity Occurs when hypersensitivity mechanisms are directed against “self” antigens Breakdown of “tolerance”

Autoimmune diseases Systemic –SLE (lupus) –Rheumatoid arthritis Organ-specific –Graves disease (thyroid) –Multiple sclerosis (brain)

Davis et al, 2011

Renal glomerulus

Group Activity

Study virtual slide, Normal kidney, PAS stain Courtesy of Dr. M Afrouzian

Study virtual slide Lupus nephritis, PAS stains Courtesy of Dr. M Afrouzian

Glomerular antibodies in SLE Anti-nucleosome Abs Anti-mesangial cell Abs Anti-collagen Abs Anti-ds DNA Abs –Among others……. Hanrotel-Saliou 2010

Histological classification of Lupus nephritis WHO Class I: Immune deposits restricted to mesangium. May be asymptomatic Class II: Mesangial immune deposits and mesangial proliferation; mild proteinuria, good prognosis Class III: Focal subendothelial immune deposits, <50% of glomeruli involved Class IV: Diffuse proliferative GN; diffuse subendothelial deposits; increased severity, frequently progresses to renal failure Class V: “Membranous” lupus nephritis; subepithelial immune deposits, renal failure is uncommon Class VI: Advanced sclerosing GN (fibrosis of glomeruli, little proliferative or inflammatory activity left)

Masutani et al, 2001