Subject: Pathology Topic: Failure of the Immune System 1 Lecturer: Dr.

Joanne Rodriguez-Pascual Date of Lecture: 26/06/2011 Transcriptionist: Bellas 01 Editor: Mommy Bellas Pages:

*when the going gets tough, the tough gets going...

IMMUNITY INNATE IMMUNITY - Present before birth, NATURAL BARRIERS skin, lining epithelium of mucosa, Langerhans CELLS: B-LYMPHOCYTES, T-LYMPHOCYTES (CD4-Helper and CD8-Cytotoxic) , MACROPHAGES (derived from Monocytes), PLASMA CELLS(modified B-cells that produce Immunoglobulins), NK CELLS CYTOKINES/CHEMOKINES chemical mediators *induce activation of inflammatory cells PLASMA PROTEINS: COMPLEMENT, COAGULATION FACTORS TOLL-LIKE RECEPTORS (TLRS) - receptors within leukocytes which recognize foreign antigens (microbes); similar to receptors found in drosophila fly ADAPTIVE IMMUNITY - Developed by exposure to pathogens, or in a broader sense, antigens - Adaptive immunity is LEARNED/ACQUIRED. It relies on PREVIOUS EXPOSURE to the pathogen or foreign antigen. - The classic types of adaptive immunity are: 1) Humoral (i.e., antibodies) *key cells -> B cells 2) Cellular (i.e., direct cellular reactions to antigens) *key cells -> T cells

*refer to last page for a bigger picture & explanation CELLS of the IMMUNE SYSTEM LYMPHOCYTES, T LYMPHOCYTES, B PLASMA CELLS (MODIFIED B CELLS) MACROPHAGES, aka HISTIOCYTES, (APCs, i.e., Antigen Presenting Cells) DENDRITIC CELLS (APCs, i.e., Antigen Presenting Cells) NK (NATURAL KILLER) CELLS

**If you wanted to make this simple you can say there are 3 types of cells, T-lymphocytes, Blymphocytes, and macrophages or APCs. **If you wanted to make it incredibly simple then just say lymphocytes and macrophages.

The fxns of lymphocytes... explanations on the next page

SY 2011-2012

B cells produce plasma cells which produces antibody (main fxn! antibody secretion) CD4 helper T cells usually requires APC for activation; can release cytokines to activate and recruit effector cells for activation of macrophages, activation of neutrophils to induce inflammation and stimulation of other B lymphocytes. CD8 cytotoxic T cells can directly kill infected cells

MAJOR HISTOCOMPATIBILITY COMPLEX A genetic LOCUS on Chromosome 6, which codes for cell surface compatibility Also called HLA (Human Leukocyte Antigens) in humans Makes sure SELF is recognized and tolerated, because the general rule of the immune system is that all UN-recognized cells will NOT be tolerated *regulates the immune system *present foreign substances to T-cells DISORDERS OF THE IMMUNE SYSTEM *mainly function to prevent the body from any harmful substances *any disorder is a result of unregulated immune system mechanism 3 BROAD CATEGORIES: Hypersensitivity reactions exaggerated response such that even substances intrinsic to body are also attacked Autoimmune diseases theres also failure to recognize self from non-self, immune system attacks normal components of the body Immunologic deficiency syndromes INNATE congenital defect; inability to produce a component of the immune system ACQUIRED such as AIDS **Amyloidosis - not a distinct entity of an immune disorder but it comes under disorders of the immune system because it results from an accumulation of immunoglobulin HYPERSENSITIVITY REACTIONS I. Immediate Hypersensitivity II. Cytotoxic Hypersensitivity A. Opsonization and Complement and Fc receptor mediated

B. Complement and Fc receptor mediated inflammation C. Antibody mediated cell dysfunction III. Immune Complex- Mediated Hypersensitivity IV. Cell Mediated Hypersensitivity A. Delayed type hypersensitivity B. T-cell mediated hypersensitivity IMMEDIATE (TYPE I) HYPERSENSITIVITY Rapidly developing immunologic reaction occurring within minutes after the combination of an antigen with an antibody bound to mast cells in individuals previously sensitized to the antigen Symptoms manifest on re-exposure Commonly referred to as ALLERGY / ATOPY Mediated by IgE antibodies directed against specific antigens (allergens) Mechanism: Ag + Ab (IgE) bound to mast cells / basophils immediate release of vasoactive amines and other mediators (Histamine) from mast cells; recruitment of inflammatory cells

*refer to last page for a bigger picture & explanation On re-exposure: Allergen binds to and cross-links the IgE on mast cells and results in: Release (degranulation) of preformed vesicles containing primary mediators Histamine (most IMPORTANT!), proteases, Chemotactic factors De novo synthesis and release of secondary mediators

 Leukotrienes B4, C4, D4; PG D2 2 PHASES: 1. Initial (rapid) response: 5-30 minutes after repeat exposure to allergen mediators: vasoactive amines (histamine)bronchial smooth muscle contraction, increased vascular permeability and dilatation, increased mucous gland secretion *Lipid mediators: LTC4 and D4 (smooth muscle contraction, increased vascular permeability), PGD2 (bronchospasm, increased mucus secretion) 2. Late (delayed ) phase : 2-24 hours after exposure - intense inflammatory cell infiltration with associated tissue damage *Cytokine mediators: TNF, IL4 GM-CSF, chemokines * Eosinophils (key mediator): cause tissue damage by releasing major basic protein and eosinophil cationic protein toxic to epithelial cells SUMMARY OF THE ACTION OF MAST CELL MEDIATORS IN IMMEDIATE (TYPE I) HYPERSENSITIVITY
Action Mediators Histamine PAF Leukotriene, C4, D4, E4 Neutral proteases that activate complement and kinins Prostaglandin D2 Leukotriene, C4, D4, E4 Histamine Prostaglandin PAF Cytokines (e.g. chemokines, TNF) Leukotriene B4 Eosinophil and neutrophil chemotactic factors

Sx: urticaria, allergic rhinitis, asthma, skin allergy SYSTEMIC ANAPHYLAXIS Secondary to parenteral or oral administration of an allergen (eg. Penicillin, peanuts, shellfish, insect toxics i.e. bee venom) More severe Pruritus, urticaria, erythema, within minutes after exposure bronchoconstriction, laryngeal edema, obstruction, hypotensive shock death

ANTIBODY-MEDIATED (TYPE II) HYPERSENSITIVITY Mediated by antibodies against intrinsic antigens or extrinsic antigens adsorbed on cell surfaces or ECM. Mechanism: Ab (IgG or IgM) + Ag (bound to cell surface or ECM) 3 MAJOR PATHWAYS: IIa. Opsonization & complement and Fc- receptormediated phagocytosis *Opsonization C3b; COATING of antigen for easier recognition for phagocytosis

Vasodilatation, increased vascular permeability

Smooth muscle spasm

Mechanism: C3b is activated, opsonizes antigen making it palatable to macrophage that recognizes it and phagocytose the infected cell **end product -> PHAGOCYTOSIS IIb. Complement- and Fc- receptor-mediated inflammation

Cellular infiltration

*notice the overlapping action of the mediators *REMEMBER HISTAMINE IMMEDIATE (TYPE I) HYPERSENSITIVITY DISORDERS LOCAL IMMEDIATE HYPERSENSITIVITY REACTIONS Exemplified by atopic allergies Hereditary predisposition Affected individuals tend to develop local type I responses to common inhaled and ingested allergens

Mechanism: Ab + Ag bound to membrane -> complement activation -> release of complement byproduct within PMNs ->activate neutrophils -> release contents (enzymes, lysosomes, ROS) which are toxic to the cells -> inflammation and tissue damage **end product -> INFLAMMATION 3

IIIc. Antibody-mediated cellular dysfunction

Mechanism: Ab against receptors of the cell -> cellular dysfunction **end product -> CELLULAR DYSFUNCTION Example: Myasthenia gravis: Ab against Ach receptors -> neurotransmitters of Ach cannot bind to receptors -> cellular dysfunction Graves disease: Ab down regulates TSH receptors -> TSH cannot bind w/ receptors -> increased TSH hormones -> Graves dx. ANTIBODY-MEDIATED (TYPE II) HYPERSENSITIVITY DISORDERS
DISEASE TARGET ANTIGEN RBC membrane proteins Platelet membrane proteins (GpIIb:IIIa or GpIb/IX) Noncollagenous protein in BM of alveoli and glomeruli Acetylcholine receptor MECHANISM IIa opsonization and phagocytosis of erythrocytes IIa opsonization & phagocytosis of platelets IIb complement and Fc receptor mediated inflammation IIc Ab inhibits Ach binding; down regulates receptors IIc antibodymediated stimulation of TSH receptors IIc Ab inhibits binding of insulin

attract neutrophils release lysosomal enzymes Systemic or local A. Systemic Immune Complex Disease Circulating immune complexes that are systemically deposited Acute serum sickness: *prototype arthritis, skin rash, fever symptoms appeared more rapidly with repeated injection of the serum Systemic Lupus Erythematosus

Autoimmune hemolytic anemia

Autoimmune thrombocytopenic purpura

Goodpasture syndrome

Myasthenia gravis

Pathogenesis PHASE I Formation of Ag-Ab complexes in the circulation PHASE II Deposition of the immune complexes in various tissues PHASE III Inflammatory reaction at the sites of immune complex deposition Clinical features appear

Graves disease (hyperthyroidism)

TSH receptor

Insulin-resistance DM (Type I)

Insulin receptor

IMMUNE-COMPLEX MEDIATED (TYPE III) HYPERSENSITIVITY *Antigen-Antibody Complexes *deposit in the blood vessels, kidneys and joints Mechanism: Ag + Ab AgAb complex (in circulation or in situ) activate complement

Mechanism of Tissue Damage in Immune-Complex Disease Exogenous A (Virus, Endogenous Ag foreign protein) (DNA) Antibody (Ag) Ag-Ab complexes (in circulation) Deposited in various organs (blood vessel, kidney, skin, joints, etc.) Ag-Ab complexes activate complement (classical pathway) Attract neutrophils and macrophages Release of lysosomal enzymes (elastase, collagenase) 4

Vasculitis, glomerulonephritis, arthritis, rash, etc. (clinical manifestations) B. Local Immune Complex Disease Disorder: Arthus reaction: localized area of tissue necrosis resulting from acute immune complex vasculitis, usually elicited in the skin Large immune complexes precipitate in the vessel walls inflammatory reaction Visible edema with severe hemorrhage followed occasionally by ulceration DISEASE ANTIGEN (Ag) INVOLVED DNA, nucleoproteins, others Hep B surface Ags Streptococcal cell wall antigen(s); may be planted in GBM Bacterial, parasite, tumor antigens Various foreign proteins Various proteins (eg foreign serum)
MANIFESTATION

A. Delayed type hypersensitivity: (CD4 + TCELLS) Principal pattern of response to TB, fungi, protozoa, and parasites, as well as contact skin sensitivity and allograft rejection Released Cytokines: i. IFN -activation of macrophages ii. IL2- proliferation of T-cells iii. TNF and lymphotoxinextravasation of lymphocytes and monocytes; granuloma formation

SLE

Nephritis, arthritis, vasculitis Vasculitis

Polyarteritis nodosa Post streptococcal glomerulone phritis

Nephritis Morphology: Perivascular cuffing aggregation of mononuclears Perivascular infiltrate replaced by macrophages (2-3weeks) epithelioid cells Granuloma formation

Nephritis

Acute glomerulone phritis Arthus reaction Serum sickness

B. T-cell mediated cytotoxicity: (CD8 + T-CELLS) Cutaneous vasculitis Arthritis, vasculitis, nephritis Response to viral infections and tumor cells, may contribute to graft rejection Mediated by 2 pathways (1) perforin-granzyme-dependent killing : preformed mediators in lysosome-like granules of CTLs Perforin can perforate the plasma membranes of the target cells that are under attack by CD8+lymphocytes. drilling holes into the membrane

T-CELL MEDIATED (TYPE IV) HYPERSENSITIVITY Initiated by antigen-activated (sensitized) lymphocytes

Granzymes delivered into target cells via perforin-induced pores. Activates caspases to Induce apoptosis. (2) Fas-fas ligand dependent killing also induces apoptosis by expression of the Fas ligand (by the activated CTLs), a molecule with homology to TNF, that can bind to Fas expressed on target cells. TRANSPLANT REJECTION Morphology (Rejection of Kidney Graft) Rejection - in which the recipient's immune system recognizes the graft as being foreign and attacks it Hyperacute Rejection minutes or hours (2 days) after transplantation, sometimes Interoperatively Due to preformed anti-donor antibodies present in the circulation of the recipient Gross: mottled, cyanotic, flaccid kidney Micro: endothelial injury (secondary to Ig and complement deposits in the vessel wall), fibrin platelet microthrombi, neutrophilic infiltrates, fibrinoid necrosis , parenchymal infarction Acute Rejection Few days or after cessation of immunosuppressive therapy Acute Cellular Rejection : (T-cell) CD8+CTL: damage tubular and vascular endothelial cells CD4+ : induce a delayed type hypersensitivity reaction interstitial mononuclear infiltrate Acute Humoral Rejection (rejection vasculitis): (B-cell) Mediated by donor Abs necrotizing vasculitis with endothelial cell necrosis extensive necrosis of renal parenchyma Chronic Rejection Months to years Progressive organ dysfunction Vascular changes Obliterative intimal fibrosis Interstitial fibrosis

Tubular atrophy with loss of renal parenchyma TYPE PROTOTYPE DISORDER Anaphylaxis; allergies, bronchial asthma (atopic forms) IMMUNE MECHANISMS Production of IgE Abs immediate release of vasoactive amines and other mediators from mast cells Production of IgG, IgM binds to Ag on target cells or tissue phagocytosis or lysis of target cell by C8,C9 (IIa), or inflammation (IIb) or cellular dysfunction (IIc) Deposition of Ag-Ab cmplexes complement activation recruitment of leukocytes release of lysosomal enzymes and toxic moieties Activated T Lymphocytes i) release of cytokines and macrophage activation; ii) T cellmediated cytotoxicity

Immediate

hypersensitivity

II Antibodymediated

AIHA (IIa) Goodpasture syndrome IIb) Graves, Myasthenia Gravis (IIc)

III Immune complex mediated

SLE, some forms of GN, serum sickness, Arthus reaction

IV Cellmediated hypersensitivity

Tubercuclosis (IVa) Response to viral infections (IVb) Transplant rejection

*NOTE: study this table

Humoral immunity - acts on extracellular microbes B cells produces plasma cells which produces antibody -> recognize pathogen, activates complement -> results in recruitment and activation of phagocytic systems (macrophages and PMNs) -> antigen-antibody complex -> eventually destroy phagocytosed microbes Cellular immunity acts intracellularly T cells (dendrites, macrophage) -> presents to microbes through T helper cells -> binding ->CD4 Thelper cells recognize presence of pathogen -> release of cytokines inducing proliferation and activation of effector cells (CD8, macrophages) wherein CD8 acts directly on cells & destroys the pathogen while macrophage phagocytose and engulf the cells On initial exposure exposure to allergen -> APC (dendritic cells) presents allergen to T cells -> detection by T cells -> release IL4, 3, 5, GM-CSF (GranulocyteMonocyte-Colony Stimulating Factor) IL4 -> IgE from B cells and these antibodies bind to mast cells At the same time, IL3, 5 recruits eosinophils and activates to release granules and mediators On re-exposure Bound IgE are CROSS-LINKED -> stimulate and trigger mast cells to release granules and mediators *granules -> damage to epithelium *mediators -> induces symptoms of an allergy