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Shock, TEI, Immuno, Neo
Shock, TE&I, Immuno, Neoplasia
Jill Conway, 9/1/00
For the lectures I taught, use your class handouts for review.
T-cells: 60-70% of peripheral lymphocytes, show TCR gene rearrangements, CD4+ (MHCII) helper cells may induce cell-mediated immunity (TH1) or humoral immunity (TH2), CD8+ cells (MHCI) are cytotoxic or suppressor cells, CD4:CD8 should be 2:1
B-cells: 10-20% lymphoctyes, show rearranged Ig genes
Macrophages: process and present antigen to T cells to induce cell-mediated immunity
NK cells: 10-15% of blood lymphocytes. No T-cell receptors on the surface, do not require previous sensitization, can kill IgG coated cells (ADCC)
Type I (Anaphylaxis):
Occurs when antigen triggers the degranulation of mast cells and/or basophils, mediated by IgE. Phase I: 5-60 minutes with vasodilation, increased vascular permeability caused by release of primary mediators (those already in preformed granules such as histamine, as well as formation of secondary mediators (leukotrienes and prostaglandins). Phase II: 2-8 hours after exposure in 50% of those exposed, with increased infiltration into area of neutrophils, eosinophils, monocytes and basophils.
Type II (Antibody Dependent):
Ab forms against normal or altered cell membrane components. May occur via complement (Ab reacts with Ag on cell surface and activates complement as in Rh reactions, transfusion reactions), via ADCC (cell coated with IgG reacts with macrophage or NK cell which lyses it), or AMCD (Ab intereferes with cell function without killing cell, as in MG and Ach receptor Ab's).
Type III (Immune Complex):
Ab-Ag complexes form which activate complement and cause accumulation of PMNs, may be systemic or localized. The complexes form, get deposited in tissues, and evoke an inflammatory response about 10 days after exposure which causes fever, joint pain, proteinuria, etc. Requires Ig forms that activate complement pathway (IgG, IgA, IgM). Arthus reaction, serum sickness, and SLE.
Type IV (Cell Mediated):
Delayed type is CD4+ cells, which secrete cytokines (especially IFN-gamma) and recruit other cells to the area as in the TB test. Note: as macrophages accumulate, they may form a granuloma, which is defined as the presence of epithelioid cells surrounded by lymphocytes. These may or may not form giant cells.
Cytotoxic form occurs when CD8+ cells sensitized to Ab kill Ab presenting cells via MHC I.
T-cell mediated involves Type IV reactions, occur within 10-14 days (unless patient is immunosuppressed), and is the acute rejection.
Ab Mediated Rejection is hyperacute (within hours), when there are preformed Abs in the recipient to donor Ags, causes vasculitis, ischemic thrombosis, and prevents graft from getting vascularized.
Caused by failure of self-tolerance, especially involving helper T-cells. Self-tolerance should occur via clonal deletion (deletion of self-reactive T and B cells through apoptosis), clonal anergy (self reactive T cells that escape deletion in the thymus are inactivated in the periphery) which occurs when Ag presenting cells do not express costimulator molecules which deactivates the T cell. This can occur with B cells as well. T cells can also be suppressed in the periphery by suppressor T cells or cytokines.
SLE: Characterized by many ANAs (not specific), including Anti-Sm and Anti-dsDNA (specific) antibodies. 10:1 females, more common and severe in African-Americans. Associated with certain HLA-DQ alleles, 30% concordance in MZ twins, however environmental factors (drugs, etc.) also play a role. ANAs attack only exposed nuclei as in damaged cells, which produces the LE body or hematoxylin body only seen in vitro. Diverse patient presentation but butterfly rash, photosensitivity, serositis, vasculitis of small arteries and arterioles, and proteinuria are common. Joints are almost always involved, with skin, kidneys (most commonly diffuse proliferative glomerulonephritis), heart, and serous membranes also often involved.
RA: Symmetrical joint involvement, especially PIP and MCP joints. The joint synovium increases, with increased vascularization and immflamatory cells and is called the pannus. May eventually lead to ankylosis. Subcutaneous nodules are common, especially on the forearm. Specific cause is unknown, but involves genetic predisposition (HLA-DR4 or DR1), some environmental insult (infection, etc.) and improper activation of T helper cells which activate macrophages that destroy tissue and B-cells which produce Abs to Fc of IgG in synovial fluid (RF). Activated CD4+ cells secrete cytokines that increase inflammation and Ab-Ag complexes form and deposit (Type III reaction). Begins with morning stiffness in joints and causes severe crippling in 15-20 years and reduced life expectancy.
Juvenile RA: Sometimes associated with HLA-B27, RF is absent.
Sjogren's Syndrome: Auto-Abs to lacrimal and salivary glands which causes xerostomia and dry eyes. Many patients also have RA or other autoimmune disease. Most patients have RF present as well as anti SS-A and SS-B (fairly specific). Anti-SS-A often causes systemic involvement in skin, kidneys, and CNS. Usually occurs in women over 40. Associated with development of lymphomas or "pseudolymphomas". Associated with HLA-DR3.
Systemic Sclerosis (scleroderma): Inflammation and fibrosis in skin and major organs (especially GI tract, lungs, and kidneys) with unknown cause. Two versions of this are diffuse which begins with skin involvement but rapidly progresses to systemic illness and limited, which mainly involves the facial and hand skin and is associated with CREST (calcinosis, Raynaud's, esophageal dysmotility, sclerodactyly, and telangiectasia). AutoAbs include Sc1-70 (DNA topoisomerase I) and anticentromere Ab (especially CREST) which are specific for this disease.
X-linked Agammaglobulinemia (Bruton's):
Occurs in males where pre-B cells fail to develop into B cells. Seen at about 6 months when maternal Abs diminish. Increased infections due to H. inf., S. Aureus, Strep. pneu, and Giardia lamblia. There are normal numbers of pre-B cells but germinal centers of lymph nodes and other lymph centers (tonsils) are underdeveloped. Autoimmune diseases occur with increased frequency, especially RA.
Isolated IgA deficiency is the most common genetic immunodeficiency. Most patients do not have symptoms although increased sinus, lung, and GI infections are possible.
Common variable deficiency is not well understood but always involves diminished Ig production, usually of all classes. Symptoms are similar to those of Bruton's but both sexes get this disease. Patients are prone to autoimmune disorders like hemolytic and pernicious anemia. Probably caused by helper T dysfunction.
Thymic Hypoplasia (DiGeorge's Syndrome):
Congenital malformation of third and fourth pharyngeal pouches so the thymus doesn't develop (as well as parathyroids which causes tetany). Infants get increased viral, fungal, and protozoal infections.
SCID: The classic "bubble boy" total absence of all T and B cell function is extremely rare, and most SCID cases result from severe T cell abnormalities so T cells fail to induce B cells and a combined deficiency results. Most common form is X-linked mutation in the gamma genes that produce many interleukins necessary for T cell development. The less common form is absence of ADA (adenosine deaminase) which helps metabolize purines and resultant accumulation of adenosine is toxic to T cells. Treat with bone marrow transplants.
Amyloidosis: This incorporates a variety of disorders which involves deposition of "amyloid" which appears as pink translucent material. Note: The definitive test for this is biopsy followed by Congo red staining, which stains amyloid pink or red and shows green birefringence under polarized light. Amyloid consists of proteins (either AL, an immunoglobulin light chain or AA, a non-immuno protein) in beta pleated sheets. AL type is associated with multiple myeloma, although most patients do not have MM. AA forms or "reactive systemic amyloidosis" is associated with chronic inflammation. There are hereditary forms as well. Kidney is the most common organ involved, and spleen is also common. Poor prognosis for systemic forms with life expectancy of 1-3 years.
HIV: Lots of immune function deficits including loss of CD4+ T cells leading to CD4:CD8 ratio inversion. It should be about 2:1 and becomes 1:2 or worse leading to increased infections, neoplasms in AIDS patients. Monocyte and macrophage function are also affected with less chemotactic and phagocytic activity, diminished ability to present antigen to T cells. AIDS is associated with polyclonal B cell activiation with circulating immune complexes. Certain infections (pneumocystis, candidiasis, toxoplasmosis, cryptococcosis) are considered AIDS defining in patients infected with HIV. Similarly, certain neoplasms cush as cervical ca, CNS lymphoma, Kaposi's are AIDS defining