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  • Plasma are B-lymphocytes that have dedicated themselves to be antibody factories.
  • The classic types of adaptive immunity are:
    Humoral
    Cellular
  • This is the outline of our entire chapter 6.
  • Desensitization therapy involves repeated injections of increasingly greater amounts of allergen, resulting in production of IgG antibodies that attach to allergens and prevent them from binding to mast cells.
  • This is a useful slide for understanding, VERY GENERALLY, which kinds of infections result from which kinds of deficiencies. As you can see, there is considerable overlap.
  • syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954.
    You should probably know the clinical presentation “profiles” of these patients with PIDS (PRIMARY Immune Deficiency Syndromes)
    Bruton’s: Males (of course) with infections, especially enteroviral, after a few months of life, after maternal antibodies are gone.
    COMMON VARIABLE: Most patients in 20’s, UTIs, LTIs
    IgA Deficiency: Usually NO symptoms
    Hyper IgM: Recurrent pyogenic infections, pneumonia, PCP, neutropenia, thrombocytopenia.
    DiGeorge: Birth defects, learning disabilities, infections, thymus problems
    SCID: Candidiasis, diaper rash, failure to thrive.
  • 14,15

    1. 1. Pathology of the immune response. Hypersensitivity reactions. Autoimmune diseases.
    2. 2. Pathology of the immune response. Immunologic deficiency syndromes. Transplantation immunity
    3. 3. Questions  Immunity. Types. Morphological basis.  Pathological immune reactions. Autoimmune diseases.  Immunologic deficiency syndromes – primary and secondary.  Transplantation immunity. Reaction of transplant rejection.
    4. 4. Immunity  INNATE (present before birth, “NATURAL”)  ADAPTIVE (developed by exposure to pathogens, or in a broader sense, antigens)
    5. 5. Innate (natural, nonspecific) immunity  Antigen-independent cells providing first defense against pathogens  Types of cells  Phagocytic cells (e.g., neutrophils, macrophages)  Natural killer cells
    6. 6. INNATE IMMUNITY  Barriers  Cells  lymphocytes, macrophages, plasma cells, NK cells  Cytokines/chemokines  Plasma proteins  Complement, Coagulation Factors  Toll-like receptors (TLR’s)
    7. 7. Acquired (specific) immunity  Antigen-dependent activation and expansion of lymphocytes  cellular  T cells are involved in cell-mediated immune responses to antigens  humoral  B lymphocytes produce antibodies
    8. 8. Cells of the Immune System  LYMPHOCYTES, T  LYMPHOCYTES, B  PLASMA CELLS (modified B cells)  MACROPHAGES (“HISTIOCYTES”)  Antigen Presenting Cells (APCs)  “DENDRITIC” CELLS  Antigen Presenting Cells (APCs)  NK (NATURAL KILLER) CELLS
    9. 9. Cells of the Immune System Cell Type Derivation Location Function T cells CD4 (helper) CD8 (cytotoxic /suppressor) Bone marrow lymphocyte stem cells mature in thymus Peripheral blood and bone marrow, thymus, paracortex of lymph nodes, Peyer's patches CD4 cells: secrete cytokines (IL-2 → proliferation of CD4/CD8 T cells; γ-interferon → activation of macrophages); help B cells become antibody-producing plasma cells CD8 cells: kill virus-infected, neoplastic, and donor graft cells B cells Bone marrow stem cells Peripheral blood and bone marrow, germinal follicles in lymph nodes, Peyer's patches Differentiate into plasma cells that produce immunoglobulins to kill encapsulated bacteria (e.g., Streptococcus pneumoniae) Act as APCs that interact with CD4 cells Natural killer cells Bone marrow stem cells Peripheral blood (large granular lymphocytes) Kill virus-infected and neoplastic cells Macrophages Conversion of monocytes into macrophages in connective tissue Connective tissue; organs (e.g., alveolar macrophages, lymph node sinuses) Involved in phagocytosis and cytokine Production Act as APCs Dendritic cells Bone marrow stem cells Skin (Langerhans' cells), germinal follicles Act as APCs
    10. 10. L Y M P H S
    11. 11. 1) ROUND NUCLEUS 2) OVOID CYTOPLASM 3) PERIPHERAL CHROMATIN 4) “CLEAR ZONE” BETWEEN NUCLEUS AND WIDER LIP OF CYTOPLASM PLASMA CELLS
    12. 12. Lymph nodes and spleen- lymphocytes B and T location
    13. 13. MACROPHAGES are MONOCYTES that have come out of circulation and have gone into tissue
    14. 14. Dendridic cells  A type of macrophage with many spiny cytoplasmic processes, found in many places  skin (Langhans cells)  brain (microglia)  They are also APC’s.
    15. 15. Natural killer cells (NK cells)  A type of cytotoxic lymphocyte  a major component of the innate immune system  NK cells play a major role in the rejection of tumors and cells infected by viruses.  The cells kill by releasing small cytoplasmic granules of proteins (perforin and granzyme)  that cause the target cell to die by  apoptosis.
    16. 16. General scheme of cellular events  APCs (Macrophages, Dendritic Cells)  T-Cells (Control Everything)  CD4 “REGULATORS” (Helper)  CD8 “EFFECTORS”  B-Cells Plasma Cells AB’s  NK Cells
    17. 17. CYTOKINES  Proteins produced by many cells -Ly and macrophages  Numerous roles in acute and chronic inflammation, and immunity  mediate innate (natural) immunity  IL-1, TNF, Interferons  regulate lymphocyte growth  many interleukins, ILs  activate inflammatory cells  stimulate hematopoesis,  Colony Stimulating Factors, CSFs
    18. 18. MHC Major Histocompatibility Complex  A genetic “LOCUS” on Chromosome 6, which codes for cell surface compatibility  Also called HLA (Human Leukocyte Antigens) in humans and H-2 in mice  It’s major job is to make sure all self cell antigens are recognized and “tolerated”, because the general rule of the immune system is that all UN-recognized cells will NOT be tolerated
    19. 19. Major Histocompatibility Complex (MHC)  Location  Short arm of chromosome 6  Human leukocyte antigen (HLA) genes  Code for HLA proteins that are unique to each individual  HLA association with disease  HLA-B27 with ankylosing spondylitis  HLA-DR2 with multiple sclerosis  HLA-DR3 and -DR4 with type 1 diabetes mellitus Class I MHC molecules  Coded by HLA-A, -B, and -C genes  Present on the membranes of all nucleated cells  Not present on mature RBCs; present on platelets  Recognized by CD8 T cells and natural killer cells Class II MHC molecules  Coded by HLA-DP, -DQ, and -DR genes  Present on antigen-presenting cells (APCs)  B cells, macrophages, dendritic cells  Recognized by CD4 T cells
    20. 20. MHC MOLECULES (Gene Products) I (All nucleated cells and platelets), cell surface glycoproteins, ANTIGENS II (APC’s, i.e., macs and dendritics, lymphs), cell surface glycoproteins, ANTIGENS III Complement System Proteins
    21. 21. IMMUNE SYSTEM DISORDERS  HYPERSENSITIVITY REACTIONS  I-IV types  “AUTO”-IMMUNE DISEASES  “collagen” diseases  IMMUNE DEFICIENCY SYNDROMES:  primary (genetic)  secondary (acquired)
    22. 22. Hypersensitivity Reactions  Pathologic or excessive reactions against an antigen are manifestations of "hypersensitivity  May result from various underlying abnormalities  Autoimmunity  Reactions against microbes  Str., tbc  Reactions against environmental antigens  pollens, animal danders, or dust mites  Chronic inflammation, is the major component of the pathology of these disorders  immune-mediated inflammatory diseases
    23. 23. Hypersensitivity Reactions  I (Immediate Hypersensitivity)  II (Antibody Mediated Hypersensitivity)  III (Immune-Complex Mediated Hypersensitivity)  IV (Cell-Mediated Hypersensitivity)
    24. 24. Hypersensitivity Reactions Reaction Pathogenesis Examples Type I IgE-dependent activation of mast cells Atopic disorders: hay fever, eczema, hives, asthma, reaction to bee sting Drug hypersensitivity: penicillin rash or anaphylaxis Type II Antibody-dependent reaction Complement-dependent reactions Lysis: ABO mismatch, Goodpasture's syndrome, hyperacute transplantation rejection Phagocytosis: warm (IgG) autoimmune hemolytic anemia, ABO and Rh hemolytic disease of newborn Complement-independent reactions Antibody (IgG, IgE)-dependent cell-mediated cytotoxicity: natural killer cell destruction of neoplastic and virus-infected cells; helminth destruction by eosinophils Antibodies directed against cell surface receptors: myasthenia gravis, Graves' disease Type III Deposition of antigen- antibody complexes Systemic lupus erythematosus (DNA-anti-DNA) Rheumatoid arthritis (IgM-Fc receptor IgG) Serum sickness (horse antithymocyte globulin-antibody) Type IV Antibody-independent T cell-mediated reactions Delayed type: contact dermatitis (e.g., poison ivy), tuberculous granuloma Cell-mediated cytotoxicity: killing of tumor cells and virus-infected cells
    25. 25. Type I (immediate) hypersensitivity  Also called allergic reactions, or allergies  Induced by environmental antigens (allergens) that stimulate strong TH2 responses and IgE production in genetically susceptible individuals  IgE coats mast cells by binding to Fcε receptors  re-exposure to the allergen leads to cross- linking of the IgE and FcεRI, activation of mast cells, and release of mediators.  Mediators are responsible for the immediate vascular and smooth muscle reactions and the late-phase reaction (inflammation).  Principal mediators are  histamine,  proteases and other granule contents  prostaglandins and leukotrienes  cytokines.  The clinical manifestations may be  local - rhinitis  systemic -anaphylaxis.
    26. 26. Type I (immediate) hypersensitivity  Allergen exposure  IMMEDIATE phase: MAST cell DEgranulation, vasodilatation, vascular leakage, smooth muscle spasm  LATE phase (hours, days): Eosinophils, PMNs, T-Cells  Clinical examples of type I hypersensitivity  Anaphylaxis,  allergies,  bronchial asthma (atopic forms)  Tests used to evaluate type I hypersensitivity  Scratch test  Positive response is a histamine-mediated wheal- and-flare reaction after introduction of an allergen into the skin.  Radioimmunosorbent test  Detects specific IgE antibodies in serum that are against specific allergens
    27. 27. Type II (cytotoxic) hypersensitivity  Antibody-dependent cytotoxic reactions  Complement-dependent reactions  Lysis  Antibody (IgG or IgM) directed against antigen on the cell membrane activates the complement system, leading to lysis by the membrane attack complex.  Phagocytosis  Fixed macrophages (e.g., in spleen) phagocytose hematopoietic cells (e.g., RBCs) coated by IgG antibodies and/or complement (C3b).  Complement-independent reactions  Antibody (IgG, IgE)-dependent cell-mediated cytotoxicity  Leukocytes with receptors for IgG or IgE lyse but do not phagocytose cells coated by antibodies.  IgG autoantibodies directed against cell surface receptors  Tests used to evaluate type II hypersensitivity  Direct Coombs' test detects IgG and/or C3b attached to RBCs.  Indirect Coombs' test detects antibodies in serum (e.g., anti-D).
    28. 28. Type II (cytotoxic) hypersensitivity Effector mechanisms  A, Opsonization of cells by antibodies and complement components, and ingestion of opsonized cells by phagocytes.  B, Inflammation induced by antibody binding to Fc receptors of leukocytes and by complement breakdown products.  C, Antireceptor antibodies disturb the normal function of receptors.  antibodies against the thyroid- stimulating hormone (TSH) receptor activate thyroid cells in Graves disease  acetylcholine (ACh) receptor antibodies impair neuromuscular transmission in myasthenia gravis.
    29. 29. Antibody-Mediated Diseases (Type II Hypersensitivity)  Autoimmune Hemolytic Anemia, AHA  Idiopathic Thrombocytopenic Purpura, ITP  Goodpasture Syndrome  Nephritis and Lung hemorrhage  Rheumatic Fever  Myasthenia Gravis  Graves Disease  Pernicious Anemia, PA
    30. 30. Type III (immunocomplex) hypersensitivity  Activation of the complement system by circulating antigen-antibody complexes  First exposure to antigen  Synthesis of antibodies  Second exposure to antigen  Deposition of antigen-antibody complexes  Complement activation, producing C5a, which attracts neutrophils that damage tissue  Arthus reaction  Localized immunocomplex reaction  Example-farmer's lung from exposure to thermophilic actinomycetes, or antigens, in air  Test used to evaluate type III hypersensitivity  Immunofluorescent staining of tissue biopsies  example-glomeruli in glomerulonephritis
    31. 31. Type III (immunocomplex) hypersensitivity  Antigen/Antibody “Complexes”  Kidney (Glomerular Basement Membrane)  Blood Vessels  Skin  Joints  Common Type III Diseases  SLE (Lupus),  Poly(Peri)arteritis Nodosa,  Poststreptococcal Glomerulonephritis,  Arthus reaction (hrs),  Serum sickness (days)
    32. 32. Type IV hypersensitivity  Antibody-independent T cell-mediated reactions (cellular immunity)  Delayed reaction hypersensitivity  CD4 cells interact with macrophages (APCs with MHC class II antigens), resulting in cytokine injury to tissue.  Cell-mediated cytotoxicity  CD8 T cells interact with altered MHC class I antigens on neoplastic, virus-infected, or donor graft cells, causing cell lysis.  Test used to evaluate type IV hypersensitivity  Patch test to confirm contact dermatitis  Example-suspected allergen (e.g., nickel) placed on an adhesive patch is applied to the skin to see if a skin reaction occurs.  Skin reaction to Candida  Clinical examples of type IV hypersensitivity
    33. 33. Type IV hypersensitivity  Mechanisms of T-cell- mediated (type IV) hypersensitivity reactions.  A, CD4+ T cells (and sometimes CD8+ cells) respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury.  B, In some diseases, CD8+ CTLs directly kill tissue cells.
    34. 34. Type IV hypersensitivity  Tuberculin Skin Reaction  DIRECT ANTIGENCELL CONTACT  GRANULOMA FORMATION  CONTACT DERMATITIS
    35. 35. SUMMARY  I Acute allergic reaction  II Antibodies directed against cell surfaces  III Immune complexes  IV Delayed Hypersensitivity (Tb skin test)
    36. 36. Autoimmune Diseases  Autoimmune dysfunction is associated with a loss of self-tolerance, resulting in immune reactions directed against host tissue.  Tolerance (unresponsiveness) to self-antigens is a fundamental property of the immune system  Central tolerance:  immature lymphocytes that recognize self-antigens in the central (generative) lymphoid organs are killed by apoptosis; I  n the B-cell lineage, some of the self-reactive lymphocytes switch to new antigen receptors that are not self-reactive.  Peripheral tolerance  mature lymphocytes that recognize self-antigens in peripheral tissues become functionally inactive (anergic), or are suppressed by regulatory T lymphocytes, or die by apoptosis.  The variables that lead to a failure of self-tolerance and the development of autoimmunity include  inheritance of susceptibility genes that may disrupt different tolerance pathways,  infections and tissue alterations that may expose self-antigens and activate APCs and lymphocytes in the tissues.
    37. 37. Mechanisms of autoimmunity  Release of normally sequestered antigens (e.g., sperm)  Sharing of antigens between host and pathogen  Defects in functions of helper or suppressor T cells  Persistence of autoreactive T and B cells  Presence of specific autoantibodies
    38. 38. CLASSIC AUTOIMMUNE DISEASES SYSTEMIC  Systemic lupus erythematosus  Rheumatoid arthritis  Sjögren syndrome  Systemic sclerosis (scleroderma)  Mixed connective tissue disease
    39. 39. CLASSIC AUTOIMMUNE DISEASES LOCAL  Hashimoto thyroiditis  Autoimmune hemolytic anemia  Multiple sclerosis  Autoimmune orchitis  Goodpasture syndrome  Autoimmune thrombocytopenia  “Pernicious” anemia  Insulin dependent diabetes mellitus  Myasthenia gravis 
    40. 40. Autoantibodies in Autoimmune Disease Autoantibodies Disease Test Sensitivity (%) Antiacetylcholine receptor Myasthenia gravis 90 Anti-basement membrane Goodpasture syndrome >90 Anticentromere CREST syndrome 30 Antiendomysial and antigliadin Celiac disease 95 Anti-insulin, Anti-islet cell Type 1 diabetes 50, 75 Anti-intrinsic factor Pernicious anemia 60 Anti-parietal cell 90 Antimicrosomal Hashimoto's thyroiditis 97 Antithyroglobulin 85 Antimitochondrial Primary biliary cirrhosis 90-100 Antimyeloperoxidase Microscopic polyangiitis 80 (p-ANCA) Antiproteinase 3 Wegener's granulomatosis >90 (c-ANCA) Antiribonucleoprotein Mixed connective tissue disease 100 Anti-TSH receptor Graves' disease 85
    41. 41. Systemic lupus erythematosus (SLE)  A systemic autoimmune disease caused by autoantibodies produced against numerous self-antigens and the formation of immune complexes.  Anti-nuclear autoantibodies, and the ones responsible for the formation of circulating immune complexes, are directed against nuclear antigens.  Other autoantibodies react with erythrocytes, platelets, and various complexes of phospholipids with proteins.  The underlying cause of the breakdown in self-tolerance in SLE is
    42. 42. Systemic lupus erythematosus (SLE)  Clinical findings  Hematologic - autoimmune hemolytic anemia, thrombocytopenia, leukopenia  Lymphatic - generalized painful lymphadenopathy, splenomegaly  Musculoskeletal - small-joint inflammation (hands) with absence of joint deformity  Skin - malar butterfly rash  Renal – 5 types, diffuse proliferative glomerulonephritis the most often  Cardiovascular - fibrinous pericarditis with or without effusion, Libman-Sacks endocarditis (sterile vegetations on mitral valve)  Respiratory interstitial fibrosis of lungs, pleural effusion with friction rub  Pregnancy-related  complete heart block in newborns  Recurrent spontaneous abortions  Drug-induced lupus erythematosus  Associated drugs - Procainamide, hydralazine
    43. 43. Systemic lupus erythematosus (SLE)  Etiology: Antibodies (ABs) directed against the patient’s own DNA, HISTONES, NON-histone RNA, and NUCLEOLUS  Pathogenesis: Progressive DEPOSITION and INFLAMMATION to immune deposits, in skin, joints, kidneys, vessels, heart, CNS  Morphology: “Butterfly” rash, skin deposits, glomerolunephritis (NOT discoid)  Clinical expression: Progressive renal and vascular disease, POSITIVE A.N.A.
    44. 44. SLE, SKIN SLE, GLOMERULUS
    45. 45. Systemic lupus erythematosus (SLE)  Laboratory findings in SLE  Antinuclear antibody (ANA) (almost all cases)  Anti-double-stranded DNA antibodies and anti-Sm antibodies  Used to confirm the diagnosis of SLE -highly specific for the disease  Antiphospholipid antibodies  Lupus anticoagulant and anticardiolipin antibodies  Damage vessel endothelium, producing vessel thrombosis  Increased incidence of strokes and recurrent spontaneous abortions  Lupus erythematosus cell  Neutrophil containing phagocytosed altered DNA  Not specific for SLE  Decreased serum complement  Used up with activation of complement system  Immunocomplexes at the dermal-epidermal junction in skin biopsies  Immunofluorescent studies identify complexes in a band-like distribution along the dermal-epidermal junction.
    46. 46. Rheumatoid Arthritis  Asystemic, chronic inflammatory disease affecting many tissues but principally attacking the joints  to produce a nonsuppurative proliferative synovitis that frequently progresses to destroy articular cartilage and underlying bone with resulting disabling arthritis  In extra-articular involvement (skin, heart, blood vessels, muscles, and lungs)-RA may resemble SLE or scleroderma  Immunology  genetic predisposition, infections  T-cell reaction, TNF –central role  Rheumatoid factor (RF or RhF) -antibody against the Fc portion of Ig G⇒ immune complexes
    47. 47. Rheumatoid Arthritis  Symmetric arthritis, principally affecting the small joints of the hands (proximal interphalangeal and metacarpophalangeal joints) and feet, ankles, knees, wrists, elbows, and shoulders.  Morphology  Pannus formation, destruction of bone, cartilage, ankylosis  synovial cell hyperplasia and proliferation;  dense perivascular inflammatory cell infiltrates (frequently forming lymphoid follicles) in the synovium composed of CD4+ T cells, plasma cells, and macrophages  increased vascularity due to angiogenesis  neutrophils and aggregates of organizing fibrin on the synovial surface and in the joint space  increased osteoclast activity in the underlying bone, leading to synovial penetration and bone erosion A pannus, formed by proliferating synovial- lining cells admixed with inflammatory cells, granulation tissue, and fibrous connective tissue
    48. 48. Rheumatoid Arthritis  Morphology  Rheumatoid subcutaneous nodules - in about one-fourth of patients, occurring along the extensor surface of the forearm or other areas subjected to mechanical pressure  rarely they can form in the lungs, spleen, heart, aorta, and other viscera.  firm, nontender, oval or rounded masses as large as 2 cm in diameter.  Microscopically, they are characterized by a central focus of fibrinoid necrosis surrounded by a palisade of macrophages, which in turn is rimmed by granulation tissue  Pleuritis/pericarditis -fibrinous  Lung - interstitial fibrosis.  Ocular changes –uveitis, keratoconjunctivitis
    49. 49. Systemic Sclerosis (Scleroderma)  Excessive production of collagen that primarily targets the skin, GIT, lungs, and kidneys  Occurs predominantly in women of childbearing age  Pathogenesis  Small-vessel endothelial cell damage produces blood vessel fibrosis and ischemic injury.  T-cell release of cytokines results in excessive collagen synthesis. clawlike appearance , ulcerations increase of compact collagen in the dermis along with thinning of the epidermis, atrophy of the dermal appendages, and hyaline thickening of the walls of dermal arterioles and capillaries
    50. 50. Systemic Sclerosis (Scleroderma)  Two groups based on its clinical course  Diffuse scleroderma, characterized by initial widespread skin involvement, with rapid progression and early visceral involvement  Limited scleroderma (CREST syndrome) - with relatively mild skin involvement, often confined to the fingers and face and involvement of the viscera occurs late  C-calcification, centromere antibody  R-Raynaud's phenomenon  E-Esophageal dysmotility  S-sclerodactyly (i.e., tapered, claw-like fingers)  T-telangiectasis (i.e., multiple punctate blood vessel dilations)  Laboratory findings in systemic sclerosis  Serum ANA is positive in 70% to 90% of cases.  Antitopoisomerase antibody –in diffuse sclerosis  Anticentromere antibodies in 30% of cases
    51. 51. Systemic Sclerosis (Scleroderma)  Clinical findings/Morphology  Raynaud's phenomenon  Sequential color changes caused by digital vessel vasculitis and fibrosis, digital infarcts  heart (cardiac Raynaud) - microvascular injury and resultant ischemia  Skin  Skin atrophy and tissue swelling beginning in the fingers and extending proximally  Extensive dystrophic calcification in subcutaneous tissue  Tightened facial features (radial furrowing around the lips)  Gastrointestinal  Dysphagia for solids and liquids  Malabsorption  Diverticula (bacterial overgrowth)  Progressive atrophy and collagenous fibrous replacement of the muscularis at any level of the gut  Respiratory  Interstitial fibrosis of lungs, respiratory failure  Renal  Vasculitis involving interlobular arteries and glomeruli, hypertension
    52. 52. Dermatomyositis /polymyositis  Immune-mediated muscle injury and inflammation  Occurs predominantly in women 40 to 60 years of age  Associated with risk of malignant neoplasms (15-20% of cases), particularly lung cancer, stomach  Pathogenesis  DM is associated with antibody-mediated damage.  PM is associated with T cell-mediated damage.  Clinical findings  Muscle pain and atrophy  large muscles of the trunk, neck, and limbs  Shoulders are commonly involved.  Heliotrope eyelids or "raccoon eyes" (purple-red eyelid discoloration)  Laboratory findings  Serum ANA is positive in fewer than 30% of cases  Jo-1 antibodies, directed against transfer RNA synthetase .  Increased serum creatine kinase  Muscle biopsy shows a lymphocytic infiltrate.
    53. 53. Polyarteritis Nodosa  A systemic vasculitis of small or medium-sized muscular arteries, typically involving renal and visceral vessels but sparing the pulmonary circulation  segmental transmural necrotizing inflammation (part of the vessel circumference)  acute phase there is transmural inflammation of the arterial wall with a mixed infiltrate of neutrophils, eosinophils, and mononuclear cells, frequently accompanied by fibrinoid necrosis  The inflammatory process weakens the arterial wall and can lead to aneurysms or even rupture  The most common manifestations are:  malaise, fever, and weight loss  hypertension, usually developing rapidly  abdominal pain and melena (bloody stool) caused by vascular GI lesions  diffuse muscular aches and pains  peripheral neuritis, predominantly affecting motor nerves  Renal (arterial) involvement –a common and a major cause of death  Biopsy is necessary to confirm the diagnosis 
    54. 54. Mixed connective tissue disease (MCTD)  Signs and symptoms similar to SLE, systemic sclerosis, and PM  distinct disease or represents heterogeneous subsets of SLE, systemic sclerosis, and PM  Renal disease is uncommon.  Immunology  Antiribonucleoprotein antibodies are positive in almost 100% of cases.
    55. 55. Sjögren Syndrome  An inflammatory disease that affects primarily the salivary and lacrimal glands, causing dryness of the mouth (xerostomia) and eyes (keratoconjunctivitis)  other secretory glands (nasopharynx, upper airway, vagina) may also be involved  extraglandular disease affecting the CNS, skin, kidneys, and muscles  increased risk for non-Hodgkin B-cell lymphoma (marginal-zonal type)  The disease is believed to be caused by an autoimmune T-cell reaction against an unknown self antigen(s) expressed in these glands, or immune reactions against the antigens of a virus that infects the tissues  autoantibodies to the ribonucleoprotein antigens SS-A (Ro) and SS-B (La)  Morphology
    56. 56. Pathology of the immune response. Immunologic deficiency syndromes. Transplantation immunity.
    57. 57. Immunodeficiency Disorders  Defects in B cells, T cells, complement, or phagocytic cells  primary (genetic)  secondary (acquired)
    58. 58. Congenital immunodeficiency disorders  B-cell disorders  Recurrent encapsulated bacterial infections (e.g., Streptococcus pneumoniae)  T-cell disorders  Recurrent infections caused by intracellular pathogens (fungi, viruses, protozoa)  Combined B- and T-cell disorders
    59. 59. Examples of Infections in Immunodeficiencies Pathogen Type T-Cell-Defect B-Cell Defect Granulocyte Defect Complement Defect Bacteria Bacterial sepsis Streptococci, staphylococci, Haemophilus Staphylococci, Pseudomonas Neisserial infections, other pyogenic bacterial infections Viruses Cytomegalovirus, Epstein- Barr virus, severe varicella, chronic infections with respiratory and intestinal viruses Enteroviral encephalitis Fungi and parasites Candida, Pneumocystis carinii Severe intestinal giardiasis Candida, Nocardia, Aspergillus Special features Aggressive disease with opportunistic pathogens, failure to clear infections Recurrent sinopulmonary infections, sepsis, chronic meningitis
    60. 60. PRIMARY Immunodeficiency Disorders  CHILDREN with repeated, often severe infections, cellular AND/OR humoral immunity problems, autoimmune defects  BRUTON (X-linked agammaglobulinemia)  Common variable immunodeficiency  IgA deficiency  Hyper IgM  DI GEORGE (THYMIC HYPOPLASIA) 22q11.2  SCID (Severe Combined Immuno Deficiency)  WISKOTT-ALDRICH  thrombocytopenia and eczema  Complement deficiencies
    61. 61. ADA= ADENOSINE DEAMINASE  Bruton’s x-linked agammaglobulemia  NO tyrosine kinase (BTK gene)  Common variable immunodeficiency  Various genetic defects, both B and T cells  IgA deficiency  Unknown  Hyper IgM  CD40-L gene defect  DiGeorge:  22q11 deletion  failure of development of 3rd and 4th pharyngeal pouch.  SCID  Early T-Cell failure Primary Immunodeficiency Disorders
    62. 62. Disease Defect(s) Clinical Features B-Cell Disorders Bruton's agammaglobulinemia Failure of pre-B cells to become mature B cells Mutated tyrosine kinase X-linked recessive disorder Sinopulmonary infections Maternal antibodies protective from birth to age 6 months ↓ Immunoglobulins IgA deficiency Failure of IgA B cells to mature into plasma cells Sinopulmonary infections, giardiasis Anaphylaxis if exposed to blood products that contain IgA ↓ IgA and secretory IgA Common variable immunodeficiency Defect in B-cell maturation to plasma cells Adult immunodeficiency disorder Sinopulmonary infections, GI infections (e.g., Giardia), pneumonia, autoimmune disease ↓ Immunoglobulins T-Cell Disorder DiGeorge syndrome Failure of third and fourth pharyngeal pouches to develop Thymus and parathyroids fail to develop Hypoparathyroidism (tetany); absent thymic shadow on radiograph; PCP Danger of GVH reaction Combined B- and T-Cell Disorders Severe combined immunodeficiency (SCID) deaminase deficiency; adenine toxic to B and T cells, ↓ deoxynucleoside triphosphate precursors for DNA synthesis Autosomal recessive disorder Defective CMI ↓ Immunoglobulins Treatment: gene therapy, bone marrow transplant (patients with SCID do not reject allografts) Wiskott-Aldrich syndrome Progressive deletion of B and T cells X-linked recessive disorder Symptom triad: eczema, thrombocytopenia, sinopulmonary infections Associated risk of malignant lymphoma Defective CMI ↓ IgM, normal IgG, ↑ IgA and IgE Ataxia-telangiectasia Mutation in DNA repair enzymes Thymic hypoplasia Autosomal recessive disorder Cerebellar ataxia, telangiectasias of eyes and skin Risk of lymphoma and/or leukemia ↑ Serum α-fetoprotein
    63. 63. Secondary Immunodeficiency Disorders  Autoimmune diseases (e.g., systemic lupus erythematosus)  Lymphoproliferative disorders (e.g., malignant lymphoma)  Infections (e.g., human immunodeficiency virus, HIV)  Immunosuppressive drugs (e.g., corticosteroids)  Radiotherapy
    64. 64. AIDS Acquired immunodeficiency syndrome  Etiology: HIV  Pathogenesis: Infection, Latency, Progressive T-Cell loss  Morphology:  Clinical Expressions: Infections, Neoplasms, Progressive Immune Failure, Death, HIV+, HIV-RNA (Viral Load)
    65. 65. EPIDEMIOLOGY  HOMOSEXUAL (40%, and declining)  INTRAVENOUS DRUG USAGE (25%)  HETEROSEXUAL SEX (10% and rising)  OTHER MODES OF TRANSMISSION  Vertical transmission - transplacental route, blood contamination during delivery, breast-feeding  Accidental needlestick  Most common mode of infection in health care workers  Blood products  Risk per unit of blood is 1 per 2 million units of blood transfused.  Body fluids containing HIV  Blood, semen, breast milk  Virus cannot enter intact skin or mucosa
    66. 66. AIDS Acquired immunodeficiency syndrome  Etiology  RNA retrovirus  HIV-1 is the most common cause in the USA  HIV-2 is the most common cause in developing countries.  Pathogenesis  HIV envelope protein (gp120) attaches to the CD4 molecule of T cells.  HIV infects CD4 T cells, causing direct cytotoxicity.  Infection of non-T cells  Can infect monocytes and macrophages in tissue (e.g., lung, brain)  Can infect dendritic cells in mucosal tissue  Dendritic cells transfer virus to B-cell germinal follicles.  Macrophages and dendritic cells are reservoirs for virus.  Loss of cell-mediated immunity  Reverse transcriptase  Converts viral RNA into proviral double-stranded DNA  DNA is integrated into the host DNA.
    67. 67. AIDS Acquired immunodeficiency syndrome  Acute phase  Mononucleosis-like syndrome 3 to 6 weeks after infection  Latent (chronic) phase  Asymptomatic period 2 to 10 years after infection  CD4 T-cell count greater than 500 cells/μL  Viral replication occurs in dendritic cells (reservoir cells) in germinal follicles of LN  Early symptomatic phase  CD4 T-cell count 200 to 500 cells/μL  Generalized lymphadenopathy  Non-AIDS-defining infections - EBV-caused glossitis, oral candidiasis  Fever, weight loss, diarrhea  AIDS  Criteria  HIV-positive with CD4 T-cell count of 200 cells/μL or less or an AIDS-defining condition  Most common AIDS-defining infections  Pneumocystis jiroveci pneumonia, systemic candidiasis  AIDS-defining malignancies  Kaposi's sarcoma, Burkitt's lymphoma (EBV), primary CNS lymphoma (EBV)  Causes of death  Disseminated infections (cytomegalovirus, Mycobacterium avium complex)
    68. 68. AIDS 1) PRIMARY INFECTION 2) LYMPHOID INFECTION 3) ACUTE SYNDROME 4) IMMUNE RESPONSE 5) LATENCY 6) AIDS
    69. 69. INFECTIONS of AIDS  Protozoal/Helminthic  Cryptosporidium, Pneumocystis Carinii Pneumonia, Toxoplasmosis  Fungal  Candida  Bacterial  TB, Nocardia, Salmonella  Viral  CMV, HSV, VZ
    70. 70. PCP
    71. 71. CRYPTOSPORIDIUM
    72. 72. CASEATING GRANULOMA
    73. 73. CANCERS of AIDS  KAPOSI SARCOMA  B-CELL LYMPHOMAS  CNS LYMPHOMAS  CERVIX CANCER, SQUAMOUS CELL
    74. 74. AIDS Acquired immunodeficiency syndrome  Immunologic abnormalities  Lymphopenia (low CD4 T-cell count)  Cutaneous anergy (defect in cell-mediated immunity)  Hypergammaglobulinemia (due to polyclonal B-cell stimulation by EBV)  CD4:CD8 ratio <1  CD4 count and risk for certain diseases  700 to 1500: normal  200 to 500: oral thrush, herpes zoster (shingles), hairy leukoplakia  100 to 200: Pneumocystis jiroveci pneumonia, dementia  Below 100: toxoplasmosis, cryptococcosis, cryptosporidiosis  Below 50: CMV retinitis, Mycobacterium avium complex, progressive multifocal leukoencephalopathy, primary central nervous system lymphoma  Pregnant women with AIDS  Treatment with a reverse transcriptase inhibitor reduces transmission to newborns to less than 8%.
    75. 75. Types of grafts  Autograft (i.e., self to self)  Associated with the best survival rate  Syngeneic graft (isograft)  Between identical twins  Allograft  Between genetically different individuals of the same species  Xenograft  Between two species  Example-transplant of heart valve from pig to human
    76. 76. Types of transplants  Cornea  Best allograft survival rate  Danger of transmission of Creutzfeldt-Jakob disease  Kidney  Better survival with kidney from living donor than from cadaver  Bone marrow  Graft contains pluripotential cells that repopulate host stem cells  Host assumes donor ABO group  Danger of graft-versus-host reaction and cytomegalovirus infection
    77. 77. Transplantation Immunology  Transplantation rejection involves a humoral or cell-mediated host response against MHC antigens in the donor graft.  There are two main mechanisms by which the host immune system recognizes and responds to the MHC molecules on the graft  Direct recognition  donor class I and class II MHC antigens on APCs in the graft are recognized by host CD8+ cytotoxic T cells and CD4+ helper T cells, respectively.  CD4+ cells proliferate and produce cytokines (e.g., IFN-γ), which induce tissue damage by a local delayed- hypersensitivity reaction.  CD8+ T cells responding to graft antigens differentiate into CTLs that kill graft cells.  Indirect recognition  graft antigens are displayed by host APCs and activate CD4+ T cells, which damage the graft by a local delayed- hypersensitivity reaction and stimulate B lymphocytes to produce antibodies. Direct pathway Indirect pathway
    78. 78. Types of rejection  On the basis of the mechanisms involved, the resulting morphology, and the tempo of the various processes, rejection reactions have been classified as:  Hyperacute (minutes)  AG/AB reaction of vascular endothelium  Acute (days months)  cellular (INTERSTITIAL infiltrate) and humoral (VASCULITIS)  Chronic (months)  slow vascular fibrosis
    79. 79. Types of rejection  Hyperacute rejection  Irreversible reaction occurs within minutes.  Pathogenesis  ABO incompatibility or action of preformed anti-HLA antibodies in the recipient directed against donor antigens in vascular endothelium  Type II hypersensitivity reaction  Pathologic finding  Vessel thrombosis  Example-blood group A person receives a blood group B heart.
    80. 80. Types of rejection  Acute rejection  Most common transplant rejection  Reversible reaction that occurs within days to weeks  Type IV cell-mediated hypersensitivity  CD4 T cells release cytokines, resulting in activation of host macrophages, proliferation of CD8 T cells, and destruction of donor graft cells.  Extensive interstitial round cell lymphocytic infiltrate in the graft, edema, and endothelial cell injury  Antibody-mediated type II hypersensitivity reaction  Cytokines from CD4 T cells promote B-cell differentiation into plasma cells, producing anti-HLA antibodies that attack vessels in the donor graft.  Vasculitis with intravascular thrombosis in recent grafts  Intimal thickening with obliteration of vessel lumens in older grafts
    81. 81. Types of rejection  Chronic rejection  Irreversible reaction that occurs over months to years  Pathogenesis  probably caused by T-cell reaction and secretion of cytokines that induce proliferation of vascular smooth muscle cells, associated with parenchymal fibrosis.  Blood vessel damage with intimal thickening and fibrosis
    82. 82. Factors enhancing graft viability  ABO blood group compatibility between recipients and donors  Absence of preformed anti-HLA cytotoxic antibodies in recipients  People must have previous exposure to blood products to develop anti-HLA cytotoxic antibodies.  Close matches of HLA-A, -B, and -D loci between recipients and donors
    83. 83. Transplantation of Hematopoietic Cells Graft-versus-host (GVH) reaction  Causes  Potential complication in bone marrow and liver transplants  Potential complication in blood transfusions given to patients with a T-cell immunodeficiency and newborns.  Pathogenesis  Donor T cells recognize host tissue as foreign and activate host CD4 and CD8 T cells.  Clinical findings  Bile duct necrosis (jaundice)  Gastrointestinal mucosa ulceration (bloody diarrhea)  Dermatitis

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