21. CELLS OF THE IMMUNE SYSTEM Present Ag to CD4 T cells Precursors to macrophage lineage; cytokine release Class II MHC expressing cells Horse-shoe shaped nucleus Found in LN, blood, lungs and other organs Antigen Presenting Cells Monocytes Phagocytose and kill bacteria Parasitic defense and allergic response ___ None Staining with eosin ___ Granulocyte; short lifespan; multilobed nucleus Bilobed nucleus; heavily granulated cytoplasm See below Phagocytic cells: PMN’s Eosinophils Macrophages Kill antibody-decorated cells and virus-infected or tumor cells (no MHC restriction) Fc receptors for antibody: CD16, CD56, CD57 Large granular lymphocytes Natural Cytolytic cells: NK cells FUNCTION MARKERS CHARACTERISTICS CELLS
22. CELLS OF THE IMMUNE SYSTEM Initiate inflammatory and acute phase response; have antibacterial, antiviral and anti-tumor activities Transport Ag to LN Efficient Ag presenters Produce cytokines Filter particles from blood Large, granular cells; Fc and C3 receptors __ __ __ __ __ Possible residence in tissue, spleen, LN, and other organs; activated by IFN- γ and TNF Presence in skin LN, tissues CNS and brain Presence in liver See below Antigen Presenting Cells Macrophages Langerhan’s cells Dendritic cells Microglial cells Kupffer cells B cells FUNCTION MARKERS CHARACTERISTICS CELLS
23. CELLS OF THE IMMUNE SYSTEM Produce IL-2, other cytokines; stimulate T-cell and B-cell growth; promote B-cell differentiation, antibody production Promotes initial defenses (local) DTH, T killer cells Promote later humoral responses CD2, CD3, T-cell receptor CD2, CD3, T-cell receptor, CD4 IL-2, IFN- γ , lympho-toxin production IL-4, IL-5, IL-6, IL-10 production Mature in Thymus; large nucleus, small cytoplasm Helper/DTH cells; Activation by APCs via Class II MHC antigen presentation TH 1 subtype TH 2 subtype Antigen-Responsive Cells T cells (all) CD4 T cells FUNCTION MARKERS CHARACTERISTICS CELLS
24. CELLS OF THE IMMUNE SYSTEM Release Histamine, provide allergic response, anti-parasitic Fc receptor for IgE Granulocytic Other cells Basophils/Mast cells Produce antibody and present antigen Terminally differentiated, antibody factories Surface antibody, Class II MHC antigens __ Mature in Peyer’s patches, BM, bursal equivalent; large nucleus, small cytoplasm; activation by Ag and T-cell factors Small nucleus, large cytoplasm Antibody-, Producing Cells B cells Plasma cells Kill viral, tumor, non-self cells; secrete TH 1 lymphokines Suppress T- cell and B-cell response CD2, CD3, T-cell receptor, CD8 CD2, CD3, T-cell receptor, CD8 Recognition of Ag presented by Class I MHC antigens Recognition of Ag presented by Class I MHC antigens Antigen-Responsive Cells CD8 T killer cells CD8 T cells (suppressor cells ) FUNCTION MARKERS CHARACTERISTICS CELLS
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32. SUBSETS OF T HELPER CELLS IN RESPONSE TO STIMULI (MAINLY CYTOKINES)
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37. HLA and Disease Association 15.0 BW47 21-Hydroxylase deficiency 5 6 20 DR3 DR4 DR3/DR4 Type I diabetes 9 DR3 Primary Sjogren syndrome 13 DR3 Chronic active hepatitis 4 DR4 Rheumatoid arthritis 14 B27 Acute anterior uveitis 14 B27 Post-gonococcal arthritis 90 B27 Ankylosing spondylitis Relative Risk HLA Allele Disease
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41. ۩ Results in tissue injury or other pathophysiological changes ۩ Occurs when an already sensitized individual is re- exposed to the same foreign substance ۩ May be immediate or delayed Hypersensitivity Reactions and Tissue Injury
42. Ensuing tissue injury may be caused by: ۩ Release of vasoactive substances ۩ Phagocytosis or lysis of cells ۩ Activation of inflammatory & cytolytic components of complement system ۩ Release of cytokines, proteolytic enzymes and other mediators of tissue injury or inflammation Hypersensitivity Reactions and Tissue Injury
138. Antibody- mediated damage to the blood vessel in a renal allograft. The blood vessel is markedly thickened and the lumen is obstructed by proliferating fibroblast and foamy macrophages.
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143. Acute cellular rejection of a renal allograft R – Intense mononuclear cell infiltrate between the glomerulus and the tubules L – Tubules undergoing destruction by invading lymphocytes
154. SOME TYPES OF TRANSPLANTS Graft contains pluripotential cells that repopulate host stem cells Host assumes donor ABO group Danger of graft-versus-host reaction and CMV infection Bone marrow Better survival with kidney from living donor than from cadaver Kidney Best allograft survival rate Danger of transmission of C-J disease Cornea COMMENTS TYPE OF TRANSPLANT
165. PERIPHERAL TOLERANCE Silence potentially autoreactive T and B cells in peripheral tissues Best defined for T cells Mechanisms: 1. Anergy 2. Suppression by regulatory T cells 3. Deletion by activation-induced cell death
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167. PERIPHERAL TOLERANCE Suppression by regulatory T cells Regulatory T cells plays a major role in preventing immune reactions against self-antigens CD4 T cells is the best defined regulatory T cells that expresses CD25, the alpha chain of the IL-2 receptor, and a transcription factor of the forkhead family (Foxp3) ***both are required for the development and maintenance of functional CD4+ regulatory T cells Mutations in Fox3p result in severe autoimmunity ***cause of autoimmune disease called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked)
168. PERIPHERAL TOLERANCE Deletion by activation-induced cell death CD4+ T cells that recognize self-antigens may receive signals that promote their death by apoptosis two mechanisms 1. Expression of a pro-apoptotic member of the Bcl family (Bim), without anti-apoptotic members of the family, Bcl-2 and Bcl-x unopposed Bim triggers apoptosis by the mitochondrial pathway 2. Involves the Fas-Fas ligand system engagement of Fas by FasL induces apoptosis of activated T cells by the death receptor pathway
179. ORGAN-SPECIFIC AUTOIMMUNE DISEASES Intrinsic factor and parietal cells BM of kidney & lung Islet cell Adrenal cortex Sperm Desmoglein in tight junctions of skin Thyroglobulin Thyroid peroxidase Pernicious anemia Goodpasture’s synd. IDDM Addison’s disease Male infertility Pemphigus Hashimoto’s Primary myxedema Antibody to cell components other than receptors Acetylcholine receptor TSH receptor Myasthenia gravis Grave’s disease Antibody to receptors Target of Immune Response Autoimmune Disease Type of Immune Response
180. NON-ORGAN SPECIFIC AUTOIMMUNE DISEASES IgG in joints dsDNA, histones RNP antigens (SS-A/Ro and SS-B/La) Myelin protein Rheumatoid arthritis SLE Sjogren’s syndrome (Sicca syndrome) Guillain-Barre synd. Antibody to cell components other than receptors Target of Immune Response Autoimmune Disease Type of Immune Response
199. Libman-Sacks endocarditis of the mitral valve in lupus erythematosus. The vegetations attached to the margin of the thickened valve leaflet are indicated by arrows.
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202. Lupus nephritis, focal proliferative type. There are two focal necrotizing lesions in the glomerulus (arrows)
203. Lupus nephritis, diffuse proliferative type. There is marked increase in cellularity throughout the glomrulus
204. Immune complex deposition in SLE. IF micrograph of a glomrulus stained with anti-IgG from a patient with diffuse proliferative lupus nephritis.
205. Immune complex deposition in SLE. Electron micrograph of a renal glomerular capillary loop showing subendothelial dense deposits corresponding to “wire loops” seen by light microscopy. Deposits are also seen in the mesangium.
206. Lupus nephritis. A glomerulus with several “wire loop” lesions representing extensive subendothelial deposits of immune complexes.
213. Multisystem manifestations of Rheumatoid arthritis. Although the initial manifestation is usually arthritis, Rheumatoid disease is a systemic illness.
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216. Rheumatoid synovitis. The synovium is swollen and shows villous pattern. There is great increase in chronic inflammatory cells in the synovial stroma, often with exudate in the joint space and fibrin deposited on the synovial surface.
217. Articular cartilage destruction. Vascular granulation tissue grows across the surface of the carilage (pannus) from the edges of the joint, and the articular surface shows loss of cartilage beneath the extending pannus.
218. The inflammatory pannus causes FOCAL DESTRUCTION OF BONE. At the edges of the joint there is osteolytic destruction of bone. This phase is associated with joint deformity.
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220. The characteristic deformity and soft tissue swelling associated with long-standing rheumatoid disease of the hands.
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224. Rheumatoid nodule. At the elbow there is a large raised subcutaneous nodule. The nodule is composed of degenerate collagen (arrow) surrounded by a chronic reaction with macrophages and giant cells, and walled off by fibrosis.
243. Multisystem manifestations of Systemic Sclerosis. Systemic Sclerosis affects a wide range of tissues and organ systems, often as a result of vascular obliteration.
244. The fingers in some patients with Systemic Sclerosis are narrowed, with tight shiny skin. Subcutaneous calcification (calcinosis cutis) can also be seen as white spots on the edges of the fingers.
Inflammation of the airways not only causes symptoms associated with widespread but variable airflow obstruction, it also results in an increase in airway hyperresponsiveness to a variety of stimuli (triggers) Environmental and genetic influences in asthma (inducers) act mainly by provoking airway inflammation, rather than directly stimulating airway hyperresponsiveness Triggers of bronchoconstriction, which are factors that provoke contraction of the sensitised airway wall, include a wide range of stimuli, such as exercise, cold air and pollen Allergens can act as both inducers and triggers
Table-5: Revised Criteria for the Classification of Systemic Lupus Erythematosus Criterion: Definition: 1. Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds 2. Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions 3.Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation 4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician 5. Arthritis Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion 6. Serositis Pleuritis - convincing history or pleuritic pain or rub heard by a physician or evidence of pleural effusion, or Pericarditis - documented by ECG or rub or evidence of pericardial effusion 7. Renal disorder Persistent proteinuria greater than 0.5 grams per day or greater than 3+ if quantitation not performed, or Cellular casts - may be red cell, hemoglobin, granular, tubular, or mixed 8. Neurologic disorder Seizures - in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance, or Psychosis - in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance 9. Hematologic disorder Hemolytic anemia - with reticulocytosis, or Leukopenia - less than 4,000/mm^3 (4.0x10^9/L) on two or more occasions, or Lymphopenia - less than 1,500/mm^3 (1.5x10^9/L) on two or more occasions, or Thrombocytopenia - less than 100,000/mm^3 (100x10^9/L) in the absence of offending drugs 10. Immunologic disorder Positive LE cell preparation, or Anti-DNA: antibody to native DNA in abnormal titer, or Anti-Sm: presence of antibody to Sm nuclear antigen, or False positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test 11. Antinuclear antibody An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with "drug-induced lupus" syndrome The proposed classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person shall be said to have systemic lupus erythematosus if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation. In 1997, anti-phospholipid antibody was added to the list of criteria for the classification of SLE (Hochberg, M.C., Arthritis Rheum 40: 1725, 1997). ( From: Tan, E.M., Cohen, A.S., Fries, J.F., et al. The 1982 revised criteria for the classification of systemic lupus erythematosus (SLE). Arthritis Rheum. 25: 1271-1277, 1982)
Table-5: Revised Criteria for the Classification of Systemic Lupus Erythematosus Criterion: Definition: 1. Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds 2. Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions 3.Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation 4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician 5. Arthritis Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion 6. Serositis Pleuritis - convincing history or pleuritic pain or rub heard by a physician or evidence of pleural effusion, or Pericarditis - documented by ECG or rub or evidence of pericardial effusion 7. Renal disorder Persistent proteinuria greater than 0.5 grams per day or greater than 3+ if quantitation not performed, or Cellular casts - may be red cell, hemoglobin, granular, tubular, or mixed 8. Neurologic disorder Seizures - in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance, or Psychosis - in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance 9. Hematologic disorder Hemolytic anemia - with reticulocytosis, or Leukopenia - less than 4,000/mm^3 (4.0x10^9/L) on two or more occasions, or Lymphopenia - less than 1,500/mm^3 (1.5x10^9/L) on two or more occasions, or Thrombocytopenia - less than 100,000/mm^3 (100x10^9/L) in the absence of offending drugs 10. Immunologic disorder Positive LE cell preparation, or Anti-DNA: antibody to native DNA in abnormal titer, or Anti-Sm: presence of antibody to Sm nuclear antigen, or False positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test 11. Antinuclear antibody An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with "drug-induced lupus" syndrome The proposed classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person shall be said to have systemic lupus erythematosus if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation. In 1997, anti-phospholipid antibody was added to the list of criteria for the classification of SLE (Hochberg, M.C., Arthritis Rheum 40: 1725, 1997). ( From: Tan, E.M., Cohen, A.S., Fries, J.F., et al. The 1982 revised criteria for the classification of systemic lupus erythematosus (SLE). Arthritis Rheum. 25: 1271-1277, 1982)
Table-5: Revised Criteria for the Classification of Systemic Lupus Erythematosus Criterion: Definition: 1. Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds 2. Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions 3.Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation 4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician 5. Arthritis Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion 6. Serositis Pleuritis - convincing history or pleuritic pain or rub heard by a physician or evidence of pleural effusion, or Pericarditis - documented by ECG or rub or evidence of pericardial effusion 7. Renal disorder Persistent proteinuria greater than 0.5 grams per day or greater than 3+ if quantitation not performed, or Cellular casts - may be red cell, hemoglobin, granular, tubular, or mixed 8. Neurologic disorder Seizures - in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance, or Psychosis - in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance 9. Hematologic disorder Hemolytic anemia - with reticulocytosis, or Leukopenia - less than 4,000/mm^3 (4.0x10^9/L) on two or more occasions, or Lymphopenia - less than 1,500/mm^3 (1.5x10^9/L) on two or more occasions, or Thrombocytopenia - less than 100,000/mm^3 (100x10^9/L) in the absence of offending drugs 10. Immunologic disorder Positive LE cell preparation, or Anti-DNA: antibody to native DNA in abnormal titer, or Anti-Sm: presence of antibody to Sm nuclear antigen, or False positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test 11. Antinuclear antibody An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with "drug-induced lupus" syndrome The proposed classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person shall be said to have systemic lupus erythematosus if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation. In 1997, anti-phospholipid antibody was added to the list of criteria for the classification of SLE (Hochberg, M.C., Arthritis Rheum 40: 1725, 1997). ( From: Tan, E.M., Cohen, A.S., Fries, J.F., et al. The 1982 revised criteria for the classification of systemic lupus erythematosus (SLE). Arthritis Rheum. 25: 1271-1277, 1982)