Path Immune System Disease FC (14)

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Path Immune System Disease FC (14)
2014-02-22 22:51:16
MBS Pathology
Exam 2
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  1. innate immunity recognizes __________, whereas the adaptive immune system recognizes __________________
    • innate immunity recognizes PATHOGENS/MICROBES
    • the adaptive immune system recognizes THINGS THAT AREN'T YOU
  2. Major Components of the Innate Immunity
    • Epithelial barriers
    • Phagocytic cells (Neutrophils, Macrophages)
    • Dendritic cells
    • Natural killer cells
    • Plasma proteins (+ the complement system)
  3. Examples of Innate Immunity
    • 1. physical barriers (skin, mucous membranes)
    • 2. biologically active substances (eg. enzymes in lysosomes, anti-microbe proteins, cytokines [IL-1, 6 & TNF-α], complement system)
    • 3. CELLS (NK cells, phagocytes [macrophages + neutrophils])
    • *present ALL the time
    • *recognizes groups of similar pathogens (NOT antigen specific)
    • *no memory: doesn't increase responsiveness with repeated exposure to pathogen
  4. What are the most important cellular reactions that can be categorized as part of the innate immune system?
    • 1. inflammation
    • 2. anti-viral defenses
  5. Principal Classes of Lymphocytes & Their Functions in Adaptive Immunity
  6. Hypersensitivity Reactions
    undesirable reactions produced by the normal immune system, including allergies, microbes, or autoimmunity
  7. Type I Hypersensitivity
    • also called IgE-mediated Hypersensitivity or Immediate Hypersensitivity
    • reaction occurs within minutes ("allergic reaction")
    • 1. upon 1st exposure to an antigen, IgE antibodies stick to mast cells through their Fc portion (mast cells & basophils have receptors for IgE Fc regions)
    • 2. upon 2nd exposure to the antigen, it cross-links 2 molecules of IgE on the surface of a mast cells causing it to degranulate
    • *it's the granules released which cause the allergic reaction
  8. Steps of an Immediate (Type I) Hypersensitivity Reaction
    • APC presents antigen fragment to TH2 subset of CD4+ helper T cell
    • TH2 T cell replicates & makes IL-4 & IL-13
    • IL-4 & IL-13 bind to their receptors on B cell surface
    • induce the B cell to make IgE
    • IgE binds to surface receptors on mast cells, sensitizing them to allergen
    • re-exposure to allergen → activation of sensitized mast cells → mediator release (vasoactive amines, AA derivatives, & later cytokines)
  9. Initial, Immediate, Rapid Response Phase
    • 1. vasodilation
    • 2. vascular leakage
    • 3. smooth muscle spasm
    • start within minutes (5-10) of a reaction, subsides by 60 minutes
    • will see microscopic edema, mast cell degranulation, + all that previously listed stuff
  10. Delayed Late-phase Reaction
    • inflammation
    • tissue destruction (sets in at ~2-8 hrs, may last for several days) from secretion/actions of lipid mediators (AAs, PGs, LTs, PAF, etc.) & cytokines released from cellular infiltration cells (neutrophils, macrophages, eosinophils, lymphocytes)
    • will see CELLular infiltrations
  11. Systemic Anaphylaxis
    • a severe & acute manifestation of type I hypersensitivity
    • symptoms include pruritus (itching), urticaria (hives), erythema followed by bronchoconstriction & laryngeal edema
    • may escalate into laryngeal obstruction, hypotensive shock, & fatal anaphylaxis w/ death in minutes to hours
    • can be caused by oral ingestion of penicillin or peanuts for example
  12. Antibody Mediated Type ll Hypersensitivity (cytotoxic reactions)
    • abnormal antibody directed against a target organ causes destruction of the target cell/organ by complement mediated lysis or ADCC
    • complement mediated lysis: Ig attached to target cell, binds complement which punches holes in cell membrane, effectively killing the cell
    • ADCC: NK cell finds/attaches to the Fc portion of the antibody & kills cell by pumping into it perforin & granzyme
    • antibody (Ig) = 'guided missile' into target cell
  13. How does antibody binding kill certain cells?
    • immune cells will recognize coated cells (or pathogens) using their Fc RECEPTORS, which bind to the Fc region of antibodies
    • engagement of a particular antibody w/ the Fc receptor on a particular cell triggers an effector function of that cell:
    • phagocytes: phagocytose
    • mast cells & neutrophils: degranulate
    • NK cells: release cytokines & cytotoxic molecules to destroy its target
  14. Opsonization
    • Fc-gamma receptors exist on some cell membranes (eg. macrophages)
    • they won't recognize free antibodies, however antibodies that bind to bacterial surfaces & CLUSTER may activate Fc-gamma receptors & PROMOTE macrophages to engulf bound bacteria
    • IgG = OPSONIN (another opsonin is C3b, which mediates opsonization via phagocyte's C3b-receptor)
  15. Examples of Type II Hypersensitivity
    • Autoimmune hemolytic anemia
    • Autoimmune thrombocytopenia
    • Goodpastures syndrome
    • Hyperacute graft rejection
    • Anti-receptor antibody diseases (eg. Myasthenia gravis, Grave’s disease)
  16. Myasthenia gravis
    • an autoantibody is made to the acetylcholine receptor (AChR) on muscle cells
    • said Ig binds to the receptor & BLOCKS binding of acetylcholine (an NT) → as result there can be no muscle activation
    • additionally, the autoantibody induces complement activation, resulting in damage to the muscle end-plate destroying AChRs as the disease progresses; also the muscle cell itself phagocytoses the antibody-receptor complex, destroying AChRs
  17. Grave’s disease (Hyperthyroidism)
    • an autoantibody to the receptor for thyroid-stimulating hormone (TSH) on cells of the thyroid
    • its binding causes constant stimulation of the thyroid, & therefore unending overproduction of the thyroid hormones T3 & T4
    • cure: remove 3/4ths of thyroid
  18. Type lll Hypersensitivity (Immune-complex Disease)
    • antigen-antibody immune complexes are trapped in the small vessels of the body, particularly in the skin, kidney, & joints
    • binding of complement to the Ig triggers an inflammatory reaction; the creation of C3a & C5a chemotactically attract neutrophils
    • neutrophils degranulate in the vessel wall releasing powerful lysosomal enzymes that serve to degrade the immune complex
    • however it simultaneously damages the vessel walls (vasculitis)
    • complement levels also drop as they're being used up/distracted by these immune complexes
  19. What type of antibodies are involved in type III hypersensitivity reactions/immune-complex diseases?
    complement fixing antibodies, aka IgG & IgM
  20. In what situation can immune-complex diseases (type III hypersensitivity reactions) NOT occur?
    if NO polymorphs (aka neutrophils) exist
  21. Systemic lupus erythematosus (SLE)
    • autoantibodies called antinuclear antibodies (ANA) are made against your own DNA (antigen = DNA)
    • immune complexes (antigen-antibody complexes) deposit in many tissues & affect many organ systems (skin, joints, serosal surfaces, kidneys, & CNS)
    • classic example of type III immune-complex disease
    • also an example of an autoimmune disease
  22. Serum Sickness
    • caused by antibodies made against contents of foreign serum from another animal (eg. a horse)
    • typically induced following therapy w/ large doses of foreign antibodies (eg. monoclonal mouse antibodies or horse serum antitoxins to cure snake bites)
    • immune complexes deposit in various tissues, especially in arteries, joints, & renal glomeruli
  23. Morphology of Type lll Hypersensitivity (Immune-complex Disease) Reactions
    • acute necrotizing vasculitis (fibrinoid necrosis)
    • specific area has a fibrinoid deposition within vessels along with neutrophil infiltration
    • surrounding the area there can be hemorrhage & edema
  24. Immune Complex Vasculitis
    necrotic vessel walls are replaced by smudgy, pink ‘fibrinoid’ material (immune complex, complement, plasma proteins)
  25. Localized Immune Complex Disease (Arthus Reaction)
    • a localized, not circulatory, type III hypersensitivity reaction
    • happens when antigen is introduced into an individual who already has pre-formed antibodies against that antigen
    • immune complexes occur at the site where antigen was introduced, attract neutrophils, & produce inflammation (in ~4-10 hours)
    • eg. tetanus booster or hypersensitivity pneumonitis (Farmer’s Lung or Bird Fancier's Disease)
  26. Delayed (Type IV) Hypersensitivity
    • delayed-type hypersensitivity (DTH) or Type IV reactions are mediated by T cells & activated macrophages (NOT antibodies)
    • the mechanisms of DTH are the same as those for cell-mediated immunity however in delayed hypersensitivity, the result is tissue damage
    • T cells release inappropriately large amounts of cytokines in response to an antigen → cytokines recruit & activate effector cells (mainly macrophages) which cause inflammation & local tissue injury
    • granulomas can form w/ persistent or non-degradable antigens
  27. Examples of Type IV Hypersensitivity
    • Type 1 diabetes mellitus
    • Multiple sclerosis
    • Rheumatoid arthritis
    • Peripheral neuropathy
    • Inflammatory bowel disease (Crohn’s disease)
    • Contact dermatitis
    • responses to Mycobacterium tuberculosis, fungi, protozoa, & parasites
    • (Guillain-Barré syndrome?)
  28. sensitization phase
    • similar to other hypersensitivity reactions, sensitization is REQUIRED to generate DTH
    • during sensitization, APCs (particularly dendritic cells) process the antigen & present it to TH1 cells
    • sensitization activates & expands the number of antigen-specific TH1 cells that can cause a DTH reaction if antigen re-exposure occurs
  29. effector phase
    • during the effector phase, T cells (antigen-specific TH1 cells) produce cytokines that recruit & activate macrophages + other inflammatory cells
    • accumulation of inflammatory cells causes local tissue damage
    • DTH reactions also involve CD8+ T cells which cause tissue damage via cell-mediated cytotoxicity
  30. Contact Dermatitis
    • skin inflammation that occurs when a foreign substance touches your skin causing irritation
    • example of delayed (type IV) hypersensitivity
  31. Granulomatous Inflammation (DTH reaction)
    • a special morphologic pattern of reaction that results from prolonged DTH reactions against persistent microbes or other stimuli
    • initial CD4+ T-cell infiltrate is replaced by activated macrophages over 2-3 weeks that look large, flat, & eosinophilic (epithelioid cells)
    • these epithelioid cells occasionally fuse under the influence of cytokines to form multinucleated giant cells
    • microscopic aggregate of epithelioid cells, typically surround by a collar of lymphocytes, is called a granuloma (older ones develop an enclosing rim of fibroblasts & connective tissue)
  32. Autoimmune Diseases
    • the response of the immune system against self-components due to a LOSS of self-tolerance
    • results in immune reactions against autologous (one's own) antigens
    • Fundamental Problem: there's an imbalance between immune activation & immune control
    • eg. Lupus, ulcerative colitis, multiple sclerosis, Crohn's disease, Sjogren's disease, rheumatoid arthritis, psoriasis, scleroderma, autoimmune hemolytic anemia
  33. Immunodeficiency Syndromes
    recurrent infections due to a breakdown in innate, humoral, or cell mediated immunity
  34. Primary Immunodeficiency Disorders
    are usually hereditary & typically manifest between 6 months & 2 yrs. of life as maternal antibody protection is lost
  35. Secondary Immunodeficiency Disorders
    • arise from altered immune function due to infections, malnutrition, aging, immunosuppression, irradiation, chemotherapy, autoimmunity, being caused by another disease, drug treatment, or environmental exposure to toxins
    • eg. Acquired Immunodeficiency Syndrome (AIDS) is a multisystem disease caused by human immunodeficiency virus (HIV)
  36. X-linked (Bruton) Agammablobulinemia
    • an X-linked disease a disease characterized by a mutated Btk, a protein tyrosine kinase that functions in the intracellular signaling pathway from the B cell receptor directing growth & differentiation of pre-B cells into B cells & plasma cells (differentiation doesn't happen)
    • results in by antibody deficiency, making a patient succesptible to bacterial infections
  37. What is found in a person who has X-linked (Bruton's) Agammablobulinemia?
    • no B cells or plasma cells in blood
    • no germinal centers in the lymph nodes
    • small lymph nodes → NO tonsils visible
    • a decrease in ALL immunoglobulin isotypes
    • *a normal number of pre-B cells in the bone marrow (in the pre-B cells of these patients, VDJ rearrangements and heavy chain (IgM & D) production are normal, but subsequent light chain gene rearrangements do NOT occur)
    • T-cell-mediated response are NORMAL
    • seen in males b/c Btk gene is on the X chromosome
  38. Why are newborn infants with X-linked (Bruton) Agammablobulinemia usually normal?
    • because protection is initially conferred by maternal antibody
    • disease typically manifests between 6 months and 2 yrs. as maternal antibody protection is lost
  39. How are patients with X-linked (Bruton's) Agammablobulinemia treated?
    • treatment is with intravenous immunoglobulin (IVIG) every ~3 weeks - contains antibodies to diseases the average population sees
    • also given good access to a doctor & antibiotics that should be administered quickly
  40. DiGeorge Syndrome (Thymic Hypoplasia)
    • defective development of third & fourth pharyngeal pouches caused by a micro-deletion on chromosome 22 (22q11) → hypoplasia of the thymus
    • patients get recurrent infections w/ intracellular bacteria, fungi, large viruses AND b/c of the lack of T cells B cells aren't activated (pyogenic infections can also occur)
    • some thymic tissue may be present & T cells may appear as a patient ages
  41. Severe Combined Immunodeficiency (SCID)
    • T cells are always abnormal but B cells may or may NOT be abnormal
    • there are numerous forms that can result from any one of several genetic defects
    • patients are susceptible to ALL infectious agents
    • treatment: reconstitution of the immune system w/ stem cell transplantation [BEWARE OF FOREIGN T CELLS GETTING IN THE TRANSPLANT → GVH]
  42. Graft Versus Host Disease (GVH)
    • a reaction of donor T cells against recipient MHC
    • CD4+ T cells in the graft are activated by allogeneic [foreign] host molecules & produce a “cytokine storm”
    • this recruits other HOST/NATIVE T cells, macrophages, & NK cells to create the severe inflammation characteristic of GVH
    • usually occurs after bone marrow transplantation
    • biliary epithelium, skin, & GI mucosa are typically damaged
    • causes suppression of normal hematopoiesis which can lead to reactivation of latent viral infections (eg. Cytomegalovirus, CMV)
  43. Hyperacute Rejection
    • happens within minutes or hours as a result of pre-formed antibodies in the recipient against the donor
    • instigated by complement binding to said pre-formed antibody & initiating powerful destruction of the tissue
    • could occur due to antibodies having been previously made against HLAs/WBCs in transfusion blood that had previously be recognized (why blood banks wash their blood and only give RBCs now)
    • could also occur to a mother who's been exposed to her baby's cells during birth, leaving her resistant to her child's & husband's HLA
    • before transplant is done need to make sure recipient doesn't have an antibody against the donor
  44. Acute Rejection
    • happens after about 10-14 days (could happen months or years) as a result of mainly cell mediated immunity but you also make some antibody to the foreign tissue
    • the recipient's T cells rejects the foreign HLA types
    • takes at least 10-14 days b/c the graft antigen has to be presented/activate T cells, T cells proliferate, make cytokines, etc. there's a build up to the immune response
  45. Chronic Rejection
    • can happen months or years after the transplant as a result of antibody, T-cell, & NK cell attack on the graft
    • due mainly to antibody made against the graft → humoral immune response
    • natural killer & T cells also attack the graft
    • occurs after an extended period of immunosuppression
    • differs from acute rejection in the degree of vascular obliteration & the amount of cellular parenchymal infiltrates (here mild or none)
  46. Acute VS. Chronic Rejection
    • Acute: mild parenchymal injury, obliterative vasculitis, cellular infiltrates
    • Chronic: parenchymal, interstitial, & vascular fibrosis, vascular smooth muscle cell proliferation, fewer cell infiltrates
  47. Amyloidosis
    • a heterogenous group of pathogenetic fibrillar proteins that accumulate within tissues & organs due to excess synthesis or resistance to degradation (when normally soluble proteins become insoluble & deposit in the extracellular space of various organs or tissues, disrupting normal function)
    • all amyloid proteins can aggregate into an insoluble, cross-beta-pleated sheet tertiary conformation extracellularly
    • accumulation of amyloid proteins can produce pressure atrophy of adjacent parenchyma
  48. AL Amyloidosis
    • stimulus: unknown, possibly a carcinogen
    • this leads to monoclonal B-cell proliferation into plasma cells which produce the soluble precursor: immunoglobulin light chains (AL = amyloid light chain)
    • the amyloid deposits contain immunoglobulin light-chains (λ, κ) derived from plasma cells, or AL protein
    • is the production of abnormal amounts of protein
  49. AA Amyloidosis
    • stimulus: chronic inflammation
    • this leads to macrophage activation → IL-1 & 6 production → stimulate liver cells to synthesize serum amyloid A protein (SAA), an acute-phase reactant that then deposits in the tissues, causing AA amyloidosis
    • the amyloid deposits contain serum amyloid A protein (SAA), or AA protein
    • is the production of abnormal amounts of protein
  50. ATTR Amyloidosis
    • stimulus: a mutation
    • a mutant form of transthyretin aggregates & deposits as ATTR protein
    • this type of amyloidosis is the product of normal amounts of mutant protein
  51. Primary Amyloidosis
    • typically found in multiple myeloma (immunocyte dyscrasias) with amyloids made up of immunoglobulin light chains (AL protein)
    • deposits can be found in the kidneys, blood vessels, & heart
  52. Secondary Amyloidosis
    • involves amyloid derived from serum amyloid-associated proteins (AA protein) produced by the liver
    • deposits can be found in the kidneys, liver, & spleen
  53. Familial Amyloidosis
    • involves amyloid made up of abnormal transthyretin
    • deposits can be found in nerves
  54. Alzheimer's disease
    beta amyloid is found deposited in neurons