Immune Diseases
Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune defici...
Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity
• “Tolerance” = unresponsiveness to an antigen• “Self-tolerance” = unresponsiveness to one’sown antigens• In generating bi...
Central tolerance• Auto-reactive T and B cells deleted during maturation• Occurs by apoptosis in thymus and bone marrow• P...
• “Autoimmunity” = immune reaction against self• Self-tolerance breaks down, causing disease• Two main reasons for breakdo...
Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseases
Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseases• Lupus
• Typical patient: young woman with butterfly rash• Symptoms unpredictable (relapsing/remitting)• Multisystem (skin, kidne...
Autoantibodies!• Antinuclear Ab present in all patients with SLE... butfound in other autoimmune diseases too• Anti-RBC, -...
They cause tissue injury!• Form immune complexes• Cause destruction, phagocytosis of cellsMultisystem effects:• Kidney (re...
• Skin involvement only• May evolve into systemic lupusDiscoid Lupus
EM of glomerular capillary loop: subendothelial deposits
Glomerulus: “wire loop” appearance
Heart valve: Libman-Sacks lesions
Heart valve: Libman-Sacks lesions
• Young woman with polyarthritis and a butterfly(or other) skin rash• Fatigue• Sensitivity to sunlight• Headaches, seizure...
Lupus: butterfly rash
Lupus: butterfly rash
Lupus facial lesions
Lupus: vasculitic rash
Lupus: “hitch-hiking thumb”
Lupus mucosal lesions
Lupus palatal lesions
• Variable! Some have few symptoms, rarepatients die within months.• Most patients: relapses/remissions overmany years.• A...
Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseases• Lupus• Rheumatoid a...
• Symmetric, mostly small-joint arthritis• Systemic symptoms (skin, heart, vessels, lungs)• Rheumatoid factor• Cytokines (...
• Genetically predisposed patient• Something (bug? self-Ag?) activates T cells• T cells release cytokines:• activate macro...
• Mainly small joints (hands), but also knees,elbows, shoulders• Symmetric; characteristic hand features• Chronic synoviti...
Rheumatoid arthritis joint lesion
Rheumatoid arthritis: villi (L) and lymphoid aggregates (R)
Rheumatoid arthritis joint deformities
• Weakness, malaise, fever• Vasculitis• Pleuritis, pericarditis• Lung fibrosis• Eye changes• Rheumatoid nodules on forearm...
Rheumatoid nodules
• Circulating IgM antibody• Directed against patient’s OWN IgG!• Forms IgM-IgG immune complexes, whichdeposit in joints an...
• Female patient with aching, stiff joints,especially in morning• Symmetric joint swelling• Fingers: ulnar deviation, swan...
Rheumatoid arthritis joint deformities
• Variable!• A few patients stabilize• Most patients have chronic course withprogressive joint destruction and disability•...
Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseases• Lupus• Rheumatoid a...
• Inflammatory disease of salivary and lacrimal glands• Dry eyes, dry mouth• T cells react against some Ag (self? viral?) ...
• CD4+ T cells attack self antigens in glands (why?!)• Autoantibodies are present, but probably are notthe primary cause o...
Salivary and lacrimal glands• enlarged• marked inflammation and gland destruction• 40x increased risk of lymphoma!Systemic...
• Female between 35-45• Enlarged salivary glands• Raynaud phenomenon• Keratoconjunctivitis sicca (dry eyes)• Oral changes:...
Sjögren syndrome: salivary gland enlargment
atrophic papillae,deeply fissuredepitheliumangular cheilitismissing teeth andmultiple cariesOral changes in Sjögren Syndrome
• Treatment is mostly supportive and symptom-based.• Oral treatment: adequate hydration, scrupulous dentalhygiene, choline...
Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseases• Lupus• Rheumatoid a...
• Excessive fibrosis throughout body: skin, viscera• Claw hands, mask-like face• Microvascular disease also present• Diffu...
• CD4+ T cells accumulate for some reason• T cells release cytokines that activate mast cells andmacrophages, which releas...
• Skin: diffuse, sclerotic atrophy. Fingers first.• GI: “rubber-hose” lower esophagus• Lungs: fibrosis, pulmonary hyperten...
Scleroderma: claw hands
Scleroderma: sclerotic skin
Scleroderma: fibrosis in alveolar walls
Scleroderma: narrowed renal vessel
• Mild skin involvement (face, fingers)• Involvement of viscera occurs later• Also called CREST syndrome• Calcinosis• Rayn...
Scleroderma: calcinosis
Scleroderma: calcinosis
Scleroderma: Raynaud phenomenon
Scleroderma: sclerodactyly
Scleroderma: telangiectasias
Scleroderma: telangiectasias
• Initial widespread skin involvement• Early visceral involvement• Rapid courseScleroderma: Diffuse Type
• Female between 50-60• Raynaud phenomenon• Stiff, clawlike fingers• Mask-like face• Difficulty swallowing• Dyspnea, chron...
Scleroderma: restricted mouth opening
• Steady, slow, downhill course over years• Limited scleroderma may exist for decadeswithout progressing• Diffuse sclerode...
Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune defici...
• Immune deficiencies• primary (inherited)• secondary (to infection, immunosuppression, etc.)• Patients more susceptible t...
• Rare!• Genetic• Can affect any part of immune system:• Adaptive (humoral or cellular)• Innate (C’, phagocytes, NK cells)...
X-linked agammaglobulinemiaSCIDSCIDDiGeorge syndromeSCIDHyper-IgM syndromeCVIDIgA deficiency
Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune defici...
• Pre-B cells can’t differentiate into B cells• Patients have no immunoglobulin• Affects males• Presents at 6 months of ag...
Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune defici...
• Group of disorders characterized by defectiveantibody production• Affects males and females equally• Presents in teens o...
Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune defici...
• Most common of all primary immune deficiencies• Cause is unknown• Most patients asymptomatic• Some patients get recurren...
Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune defici...
• Patients make normal (or even increased) amounts of IgM• But can’t make IgG, IgA, or IgE!• X-linked in most cases• Patie...
Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune defici...
• Developmental malformation affecting 3rd and 4thpharyngeal pouches• Thymus doesn’t develop well• Patients don’t have eno...
Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune defici...
• Group of syndromes with both humoral and cell-mediated immune defects• Patients get all kinds of infections• Lots of ver...
Disease Transmission Defect Clinical stuffXLA X-linkedNo mature B cells;no IgInfant with recurrentbacterial infectionsCVID...
Immune diseases
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Immune diseases

  1. 1. Immune Diseases
  2. 2. Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune deficiencies• Basic concepts• Specific diseases
  3. 3. Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity
  4. 4. • “Tolerance” = unresponsiveness to an antigen• “Self-tolerance” = unresponsiveness to one’sown antigens• In generating billions of B and T cells, some willreact against self antigens!• There are two ways of muzzling these cells:central tolerance and peripheral toleranceImmunologic Tolerance
  5. 5. Central tolerance• Auto-reactive T and B cells deleted during maturation• Occurs by apoptosis in thymus and bone marrow• Process not perfect (some get out!)Peripheral tolerance• Auto-reactive cells muzzled in peripheral tissues• Some become “anergic” (inactive) in periphery• Some are suppressed by regulatory T cells• Some undergo apoptosis when activatedImmunologic Tolerance
  6. 6. • “Autoimmunity” = immune reaction against self• Self-tolerance breaks down, causing disease• Two main reasons for breakdown:Genes• HLA-DR4: ↑ risk of rheumatoid arthritis• HLA-B27: ↑ risk of ankylosing spondylitisEnvironmental triggers• Expose hidden self-antigens• Activate APCs• Mimic self antigensAutoimmunity
  7. 7. Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseases
  8. 8. Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseases• Lupus
  9. 9. • Typical patient: young woman with butterfly rash• Symptoms unpredictable (relapsing/remitting)• Multisystem (skin, kidneys, joints, heart)• Antinuclear antibodiesThings You Must KnowLupus
  10. 10. Autoantibodies!• Antinuclear Ab present in all patients with SLE... butfound in other autoimmune diseases too• Anti-RBC, -lymphocyte, -platelet, or –phospholipidantibodies may be present tooUnderlying cause unclear• Genetic predisposition…• …plus triggers (UV radiation, drugs)Lupus Etiology
  11. 11. They cause tissue injury!• Form immune complexes• Cause destruction, phagocytosis of cellsMultisystem effects:• Kidney (renal failure)• Skin (“butterfly rash”)• CNS (focal neurologic deficits)• Joints (arthritis)• Heart (pericarditis, endocarditis)What’s so bad about having these autoantibodies?
  12. 12. • Skin involvement only• May evolve into systemic lupusDiscoid Lupus
  13. 13. EM of glomerular capillary loop: subendothelial deposits
  14. 14. Glomerulus: “wire loop” appearance
  15. 15. Heart valve: Libman-Sacks lesions
  16. 16. Heart valve: Libman-Sacks lesions
  17. 17. • Young woman with polyarthritis and a butterfly(or other) skin rash• Fatigue• Sensitivity to sunlight• Headaches, seizures, or psychiatric problems• Pleuritic chest pain• Unexplained fever• Oral lesions (rare): nonspecific, red-white, erosiveLupus: Things a Dentist Might See
  18. 18. Lupus: butterfly rash
  19. 19. Lupus: butterfly rash
  20. 20. Lupus facial lesions
  21. 21. Lupus: vasculitic rash
  22. 22. Lupus: “hitch-hiking thumb”
  23. 23. Lupus mucosal lesions
  24. 24. Lupus palatal lesions
  25. 25. • Variable! Some have few symptoms, rarepatients die within months.• Most patients: relapses/remissions overmany years.• Acute flare-ups controlled with steroids• 80% 10-year survival• Most common cause of death: renal failureLupus Prognosis
  26. 26. Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseases• Lupus• Rheumatoid arthritis
  27. 27. • Symmetric, mostly small-joint arthritis• Systemic symptoms (skin, heart, vessels, lungs)• Rheumatoid factor• Cytokines (especially TNF) cause damageThings You Must KnowRheumatoid Arthritis
  28. 28. • Genetically predisposed patient• Something (bug? self-Ag?) activates T cells• T cells release cytokines:• activate macrophages (causing destruction)• cause B cells to make antibodies against joint• Most important of these cytokines: TNF• Cytokines cause inflammation and tissue damageRA Etiology
  29. 29. • Mainly small joints (hands), but also knees,elbows, shoulders• Symmetric; characteristic hand features• Chronic synovitis with pannus formation:• synovial cell proliferation• inflammation• granulation tissueRA Joint Disease
  30. 30. Rheumatoid arthritis joint lesion
  31. 31. Rheumatoid arthritis: villi (L) and lymphoid aggregates (R)
  32. 32. Rheumatoid arthritis joint deformities
  33. 33. • Weakness, malaise, fever• Vasculitis• Pleuritis, pericarditis• Lung fibrosis• Eye changes• Rheumatoid nodules on forearmsRA Systemic Disease
  34. 34. Rheumatoid nodules
  35. 35. • Circulating IgM antibody• Directed against patient’s OWN IgG!• Forms IgM-IgG immune complexes, whichdeposit in joints and cause badness• Present in 80% of patientsRheumatoid Factor
  36. 36. • Female patient with aching, stiff joints,especially in morning• Symmetric joint swelling• Fingers: ulnar deviation, swan-neck deformities,boutonniere deformities• Rheumatoid nodulesRA: Things a Dentist Might See
  37. 37. Rheumatoid arthritis joint deformities
  38. 38. • Variable!• A few patients stabilize• Most patients have chronic course withprogressive joint destruction and disability• Lifespan shortened by 10-15 years• Treatment: steroids, anti-TNF agentsRA: Prognosis
  39. 39. Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseases• Lupus• Rheumatoid arthritis• Sjögren syndrome
  40. 40. • Inflammatory disease of salivary and lacrimal glands• Dry eyes, dry mouth• T cells react against some Ag (self? viral?) in gland;gland gets destroyed• Increased risk of lymphomaThings You Must KnowSjögren Syndrome
  41. 41. • CD4+ T cells attack self antigens in glands (why?!)• Autoantibodies are present, but probably are notthe primary cause of tissue injury• ANAs• RF• Anti-SS-A, anti-SS-B• Viral trigger?• Genetic predispositionSjögren Etiology
  42. 42. Salivary and lacrimal glands• enlarged• marked inflammation and gland destruction• 40x increased risk of lymphoma!Systemic disease• fatigue• arthralgia/myalgia• Raynaud phenomenon• vasculitis• peripheral neuropathy• often, patient has another autoimmune disease tooSjögren Signs and Symptoms
  43. 43. • Female between 35-45• Enlarged salivary glands• Raynaud phenomenon• Keratoconjunctivitis sicca (dry eyes)• Oral changes:• Xerostomia (dry mouth)• mucosal atrophy• candidiasis• mucosal ulceration• dental caries• taste dysfunctionSjögren: Things a Dentist Might See
  44. 44. Sjögren syndrome: salivary gland enlargment
  45. 45. atrophic papillae,deeply fissuredepitheliumangular cheilitismissing teeth andmultiple cariesOral changes in Sjögren Syndrome
  46. 46. • Treatment is mostly supportive and symptom-based.• Oral treatment: adequate hydration, scrupulous dentalhygiene, cholinergic agents (stimulate saliva release),frequent dental exams• Eye treatment: lubricating solutions, surgical procedures• Systemic symptom treatment: steroids, otherimmunosuppressive drugsSjögren Treatment
  47. 47. Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseases• Lupus• Rheumatoid arthritis• Sjögren syndrome• Scleroderma
  48. 48. • Excessive fibrosis throughout body: skin, viscera• Claw hands, mask-like face• Microvascular disease also present• Diffuse and limited typesThings You Must KnowScleroderma (Systemic Sclerosis)
  49. 49. • CD4+ T cells accumulate for some reason• T cells release cytokines that activate mast cells andmacrophages, which release fibrogenic cytokines• B cell activation also occurs (diagnostic antibody:anti-Scl 70) but doesn’t play major role• The cause of microvascular changes is unknownScleroderma Etiology
  50. 50. • Skin: diffuse, sclerotic atrophy. Fingers first.• GI: “rubber-hose” lower esophagus• Lungs: fibrosis, pulmonary hypertension• Kidneys: narrowed vessels, hypertension• Heart: myocardial fibrosisScleroderma Signs and Symptoms
  51. 51. Scleroderma: claw hands
  52. 52. Scleroderma: sclerotic skin
  53. 53. Scleroderma: fibrosis in alveolar walls
  54. 54. Scleroderma: narrowed renal vessel
  55. 55. • Mild skin involvement (face, fingers)• Involvement of viscera occurs later• Also called CREST syndrome• Calcinosis• Raynaud phenomenon• Esophageal dysmotility• Sclerodactyly• Telangiectasia• Benign courseScleroderma: Limited Type
  56. 56. Scleroderma: calcinosis
  57. 57. Scleroderma: calcinosis
  58. 58. Scleroderma: Raynaud phenomenon
  59. 59. Scleroderma: sclerodactyly
  60. 60. Scleroderma: telangiectasias
  61. 61. Scleroderma: telangiectasias
  62. 62. • Initial widespread skin involvement• Early visceral involvement• Rapid courseScleroderma: Diffuse Type
  63. 63. • Female between 50-60• Raynaud phenomenon• Stiff, clawlike fingers• Mask-like face• Difficulty swallowing• Dyspnea, chronic cough• Difficulty getting dentures inScleroderma: Things a Dentist Might See
  64. 64. Scleroderma: restricted mouth opening
  65. 65. • Steady, slow, downhill course over years• Limited scleroderma may exist for decadeswithout progressing• Diffuse scleroderma is more common and hasworse prognosis• Overall 10-year survival = 35-70%Scleroderma Prognosis
  66. 66. Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune deficiencies• Basic concepts
  67. 67. • Immune deficiencies• primary (inherited)• secondary (to infection, immunosuppression, etc.)• Patients more susceptible to infections and cancer• Type of infection varies:• Ig, C’ or phagocytic cell defect: bacterial infection• T cell defect: viral and fungal infections• This lecture covers primary immune deficienciesBasic Concepts
  68. 68. • Rare!• Genetic• Can affect any part of immune system:• Adaptive (humoral or cellular)• Innate (C’, phagocytes, NK cells)• Typical patient: infant with recurrent infections• Primary importance for our class: boardsPrimary Immune Deficiencies
  69. 69. X-linked agammaglobulinemiaSCIDSCIDDiGeorge syndromeSCIDHyper-IgM syndromeCVIDIgA deficiency
  70. 70. Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune deficiencies• Basic concepts• Specific diseases• X-linked agammaglobulinemia
  71. 71. • Pre-B cells can’t differentiate into B cells• Patients have no immunoglobulin• Affects males• Presents at 6 months of age (maternal Ig gone)• Recurrent bacterial infections• Treatment: intravenous pooled human IgX-Linked Agammaglobulinemia
  72. 72. Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune deficiencies• Basic concepts• Specific diseases• X-linked agammaglobulinemia• Common variable immunodeficiency
  73. 73. • Group of disorders characterized by defectiveantibody production• Affects males and females equally• Presents in teens or twenties• Basis of Ig deficiency is variable (hence the name)and often unknown• Patients more susceptible to infections, but alsoto autoimmune disorders and lymphoma!Common Variable Immunodeficiency
  74. 74. Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune deficiencies• Basic concepts• Specific diseases• X-linked agammaglobulinemia• Common variable immunodeficiency• Isolated IgA deficiency
  75. 75. • Most common of all primary immune deficiencies• Cause is unknown• Most patients asymptomatic• Some patients get recurrent sinus/lung infections or diarrhea(IgA is the major Ig in mucosal secretions)• Possible anaphylaxis following blood transfusion (patientshave anti-IgA antibodies, and there is IgA in transfusedblood!)• Increased incidence of autoimmune disease (who knows why)Isolated IgA Deficiency
  76. 76. Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune deficiencies• Basic concepts• Specific diseases• X-linked agammaglobulinemia• Common variable immunodeficiency• Isolated IgA deficiency• Hyper-IgM Syndrome
  77. 77. • Patients make normal (or even increased) amounts of IgM• But can’t make IgG, IgA, or IgE!• X-linked in most cases• Patients also have a defect in cell-mediated immunity• Patients have recurrent bacterial infections and infectionswith intracellular pathogens (Pneumocystis jiroveci)Hyper-IgM Syndrome
  78. 78. Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune deficiencies• Basic concepts• Specific diseases• X-linked agammaglobulinemia• Common variable immunodeficiency• Isolated IgA deficiency• Hyper-IgM Syndrome• DiGeorge Syndrome
  79. 79. • Developmental malformation affecting 3rd and 4thpharyngeal pouches• Thymus doesn’t develop well• Patients don’t have enough T cells• Infections: viral, fungal, intracellular pathogens• Patients may also have parathyroid hypoplasia• Treatment: thymus transplant!DiGeorge Syndrome
  80. 80. Immune Diseases OutlineAutoimmune diseases• Immunologic tolerance and autoimmunity• Specific diseasesPrimary immune deficiencies• Basic concepts• Specific diseases• X-linked agammaglobulinemia• Common variable immunodeficiency• Isolated IgA deficiency• Hyper-IgM Syndrome• DiGeorge Syndrome• Severe combined immunodeficiency
  81. 81. • Group of syndromes with both humoral and cell-mediated immune defects• Patients get all kinds of infections• Lots of very different genetic defects• Half of cases are X-linked• Treatment: bone marrow transplantationSevere Combined Immunodeficiency
  82. 82. Disease Transmission Defect Clinical stuffXLA X-linkedNo mature B cells;no IgInfant with recurrentbacterial infectionsCVIDIgA deficiencyHyper-IgMDiGeorgeSCIDImmune Diseases Outline
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