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IHO Week 5 > Immune Diseases Lecture 2 > Flashcards

Immune Diseases Lecture 2 Flashcards

1
Q

What lab test would you do to see if someone has antibody deficiencies (B-cell function)?

A

Immunoglobulin levels

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2
Q

What test would you do to see if someone has cellular immunity deficiencies (T-cell function)?

A

In addition to CBC, can use flow cytometry, skin testing with candida antigen to assess cutaneous delayed-type hypersensitivity (DTH) response.

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3
Q

What test would you do to see if someone has phagocytic disorders?

A

CBC, peripheral smear (giant azurophilic granules in neutrophils, eosinophils, and other granulocytes are characteristic of Chediak-Higashi syndrome), genetic tests, specific tests of neutrophil function.

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4
Q

What tests would you do to see if someone has complement activity disorders?

A

Total serum complement (CH50)

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5
Q

What are three ways to know if a patient has an immunodeficiency?

A
  1. Clinical history - patient has condition associated with immunodeficiency
  2. Patient presents with an opportunistic infection from a “signature organism” - that indicates a compromised immune system. These are infections caused by organisms that usually don’t cause disease but become pathogenic when the body’s immune system is impaired. (ex: pneumonia due to pneumocystis jiroveci, prolonged and severe oral candidiasis, invasive aspergillus, etc.)
  3. Patient presents with repeated infections or other symptoms that suggest immunodeficiency.
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6
Q

What are the causes of secondary immunodeficiency?

A
  1. Immunosuppressive therapy (medications):
    - Cytotoxic therapy for malignancy
    - Treatment of autoimmune disease
    - Bone marrow ablation prior to transplanatation
    - Treatment or prophylaxis of graft vs. host disease
    - Treatment of rejection following solid organ transplant
  2. Microbial infection (ex: HIV/AIDS)
    - Infection with HIB results in marked immune suppression, primarily from selective infection and loss of CD4+ helper T lymphocytes (affects cell-mediated immunity)
  3. Malignancy (disease-related immunosuppression)
  4. Disorders of biochemical homeostasis
  5. Autoimmune disease (e.g. SLE, RA)
  6. Severe burn injury
  7. Exposure to radiation, toxic chemicals
  8. Asplenia/hyposplenism
  9. Aging
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7
Q

What types of malignancy cause secondary immunodeficiency?

A
  • Hodgkin’s disease, CLL (e.g. hypogammaglobulinemia in chronic lymphocytic leukemia)
  • Multiple myeloma
  • Malignancy of solid tumors (tumor-derived immunosuppressive factors)
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8
Q

What disorders of biochemical homeostasis cause secondary immunodeficiency?

A
  • Diabetes (multifactorial, including decreased neutrophil function and impaired cytokine production from macrophages)
  • Renal insufficiency/dialysis
  • Hepatic insufficiency/cirrhosis
  • Malnutrition (affects many components of the immune system)
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9
Q

What type of infection are patients without a spleen at risk for and why?

A
  • Bacterial infection with encapsulated organisms (Streptococcus pneumoniae - these patients get vaccinations for S. pneumoniae, H. influenzae, N. meningitidis)
  • Loss of splenic macrophages post splenectomy can lead to increased risk of bacterial infection
  • May come into hospital with severe sepsis
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10
Q

What 3 B-cell congenital immunodeficiency disorders should you know?

A
  • Bruton’s agammaglobulinemia
  • IgA deficiency
  • Common variable immunodeficiency
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11
Q

What 1 T-cell congenital immunodeficiency disorder should you know?

A

DiGeorge Syndrome

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12
Q

What 3 Combined B- and T-Cell congenital immunodeficiency disorders should you know?

A
  • Severe combined immunodeficiency (SCID)
  • Wiskott-Aldrich Syndrome
  • Ataxia-telangiectasia
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13
Q

What is the pathogenic defect behind Bruton’s agammaglobulinemia?

A
  • Failure of pre-B cells to become mature B cells
  • Mutated tyrosine kinase
  • X-linked recessive disorder
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14
Q

What is the pathogenic defect behind IgA deficiency?

A

-Failure of IgA B cells to mature into plasma cells

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15
Q

What is the pathogenic defect behind Common variable immunodeficiency?

A
  • Defect in B-cell maturation to plasma cells

- Adult immunodeficiency disorder

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16
Q

What is the pathogenic defect behind DiGeorge syndrome?

A
  • Failure of third and fourth pharyngeal pouches to develop

- Thymus and parathyroid glands fail to develop

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17
Q

What is the pathogenic defect behind Severe combined immunodeficiency (SCID)?

A
  • Adenosine deaminase deficiency (15%); autosomal recessive disorder; adenine toxic to B and T cells; Dec. deoxynucleoide triphosphate precursors for DNA synthesis
  • Other disorders: stem cell defect
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18
Q

What is the pathogenic defect behind Wiskott-Aldrich syndrome?

A
  • Progressive deletion of B and T cells

- X-linked recessive disorder

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19
Q

What is the pathogenic defect behind Ataxia-telangiectasia?

A
  • Mutation in DNA repair enzymes
  • Thymic hypoplasia (underdevelopment/incomplete development)
  • Autosomal recessive disorder
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20
Q

What is the difference between primary and secondary immunodeficiencies?

A
  1. Primary - congenital i.e. genetically determined

2. Secondary - due to complications of cancer, infection, malnutrition, immunosuppression, irradiation, or chemotherapy

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21
Q

In what patient population does one typically encounter primary immunodeficiencies?

A
  • Many primary immunodeficiency states manifest themselves in infancy, between 6 months and 2 years of life
  • They are detected as a result of multiple recurrent infections
  • Primary immunodeficiencies can affect either T or B lymphocyte functions in adaptive immunity or defense mechanisms in innate immunity
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22
Q

What clinical features are associated with Bruton’s agammaglobulinemia?

A

-SP - spinopulmonary infections
-Maternal antibodies protective from birth to age 6 months
Lab = Dec. Immunoglobulins

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23
Q

What clinical features are associated with IgA deficiency?

A

-SP - spinopulmonary infections; giardiasis
-Anaphylaxis if exposed to blood products that contain IgA
Lab = Dec. IgA and secretory IgA

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24
Q

What clinical features are associated with common variable immunodeficiency?

A
  • Sinopulmonary infections (90-100%), GI infections (e.g., Giardia), pneumonia, autoimmune disease (ITP-idiopathic thrombocytopenic purpura, AIHA-autoimmune hemolytic anemia), malignancy (25%)
  • Common pathogens: Actinomyces israeli, Streptococcus pneumoniae, Haemophilus influenzae, chronic infections - staphylococcus aureus, Pseduomonase aeruginosa
  • Dec. Immunoglobulins
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25
Q

What is autoimmune disease?

A

Autoimmune diseases are immune-mediated inflammatory disease in which tissue and cell injury are due to immune reactions to self-antigens (autoimmunity).
-Disease may be mediated by:
–Autoantibodies
–Immune complexes
–T lymphocytes
Presence of autoantibodies does not always indicate presence of autoimmune disease (healthy people have some autoantibodies)

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26
Q

What is the key underlying immune defect behind autoimmune disease?

A

Loss of self-tolerance!

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27
Q

What is self-tolerance?

A

It refers to the phenomenon of unresponsiveness to an individual’s own antigens as a result of exposure to lymphocytes to that antigen.

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28
Q

What two key factors combined together lead to autoimmune disease?

A

Autoimmunity arises from a combination of (1) the inheritance of susceptibility genes, which may contribute to the breakdown of self-tolerance and (2) environmental triggers, such as infections and tissue damage which promote activation of self-reactive lymphocytes.

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29
Q

How can infections cause autoimmunity?

A
  1. Infections may up-regulate the expression of co-stimulators of APC’s, and if these cells are presenting self-antigens, there may be a breakdown of anergy and activation of T cells specific for the self antigens.
  2. Offending organism may express antigens that have the same amino acid sequence of self antigens. This can result in immune response to self antigens and the process known as molecular mimicry (e.g. Rheumatic heart disease in which antibodies against streptococcal proteins react with myocardial proteins producing myocarditis)
  3. Some viruses (EBV and HIV) cause polyclonal B lymphocyte activation which may result in the production of autoantibodies.
  4. Tissue injury due to the infection may release self antigens and also structurally alter self antigens so that they are able to activate T lymphocytes.
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30
Q

What is the typical clinical course of untreated autoimmune disease?

A

Autoimmune diseases, once initiated, tend to be progressive. While there may be sporadic relapses and remissions, there is usually inexorable tissue damage if untreated.

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31
Q

What is the underlying pathologic mechanism of systemic lupus erythematosis (SLE)?

A

SLE is a disease involving multiple organs, characterized by the formation of multiple autoantibodies, particularly anti-nuclear antibodies (ANA’s), in which injury is caused mainly by deposition of immune complexes and binding of antibodies to various cells and tissues.

32
Q

What autoantibodies are associated with SLE?

A

Anti-nuclear antibodies (ANA’s)

33
Q

What is used to diagnose SLE?

A

Immunoassay (ANA test) and indirect immunofluorescence can be used to detect anti-nuclear antibodies (ANA’s).
-The pattern of nuclear fluorescence suggests the type of anti-nuclear antibody present

34
Q

What is virtually diagnostic for SLE?

A

Antibodies for dsDNA and Smith (Sm) antigen

35
Q

What are most lesions in SLE caused by?

A

Immune complex deposition (type III hypersensitivity)

36
Q

What other types of antibodies can SLE patients have?

A

Antibodies directed against red cells, platelets, white cells —-> causes cytopenias (antibody mediated (type II) hypersensitivity)

37
Q

What potential complications can arise from the presence of anti-phospholipid antibodies in SLE?

A
  • Anti-phospholipid antibodies may produce a false positive syphilis test and can prolong the partial thromboplastin time (lupus anticoagulant)
  • Anti-phospholipid antibodies are associated with a hyper coagulable state: Patients can get venous and arterial thrombosis (blood clot), resulting in spontaneous miscarriages and cerebral ischemia (secondary anti-phospholipid antibody syndrome)
38
Q

Why can SLE involve multiple organ systems?

A

Loss of self tolerance and persistence of nuclear antigens leads to the formation of antigen-antibody complexes, which are deposited from blood stream into any tissues, leading to injury (primarily an immune complex-mediated disease, type III hypersensitivity)

39
Q

What are the pathologic findings in SLE?

A
  1. Acute necrotizing vasculitis - can affect any organ!
  2. Kidney (lupus nephritis): due to immune complex deposition in the glomeruli, tubular or peritubular capillary basement membranes, or larger blood vessels. A variety of patterns of glomerular injury are seen.
  3. Skin: erythema in light exposed areas, typically immune complex deposition at the dermoepidermal junction
  4. Joints: non-erosive, non-deforming small joint involvement (in contrast to RA)
  5. Cardiovascular: fibrinous pericarditis, non-bacterial verrucous endocarditis; accelerated coronary atherosclerosis in long-term disease
  6. Spleen: splenomegaly
  7. Lungs: pleuritis, pleural effusion, interstitial fibrosis
40
Q

What is the pneumonic for clinical findings in SLE?

A

SOAP BRAIN MD

41
Q

What is SOAP BRAIN MD?

A 
S - Serositis
O - Oral ulcers
A - Arthritis
P - Photosensitvity, pulmonary fibrosis
B - Blood cells
R - Renal, Raynauds
A - ANA
I - Immunologic (anti-Sm, anti-dsDNA)
N - Neuropsych
M - Malar rash
D - Discoid rash
42
Q

What is a diagnostic test for RA?

A

Presence of antibodies to cyclic citrullinated proteins (CCPs) - these proteins may be produced during infection

43
Q

What are the pathologic findings seen in the involved joints and in rheumatoid nodules?

A

The systemic inflammatory disorder causes nonsuppurative proliferative and inflammatory synovitis.
-Synovitis often progresses to destruction of the articular cartilage and ankylosis (stiffening or immobility) of the joints

44
Q

What is the pathologic mechanism in rheumatoid arthritis?

A

Pathogenesis is uncertain.

  • RA thought to be triggered by exposure to an arthritogenic (arthritis causing) antigen in a genetically predisposed individual that results in a breakdown of immunological self-tolerance and a chronic inflammatory reaction.
  • Initial arthritis leads to a continuing autoimmune reaction, with activation of CD4+ helper T-cell and the release of inflammatory mediators and cytokines that ultimately destroy the joint.
  • In addition to a T cell response, there is also a B cell response, producing autoantibodies.
45
Q

What is Sjogren syndrome? What is its pathogenesis?

A
  • Chronic disease of dry eyes and dry mouth resulting from autoimmune, immunological mediated destruction of the lacrimal glands and salivary glands. It can occur as an isolated disease (primary) or in associated with another autoimmune disorder (secondary - ex: RA most common association)
  • Pathogenesis unknown but thought to be related to aberrant T and B cell activation in genetically susceptible individuals (possible trigger: viral infection in salivary glands)
46
Q

What are the clinical findings associated with Sjogren syndrome?

A
  • Usually occurs in middle aged women
  • Lymphocytic inflammation of lacrimal and salivary glands followed by fibrosis and gland atrophy as disease develops
  • May see parotid gland enlargement due to inflammation
  • Some patients show extra glandular disease like synovitis, diffuse pulmonary fibrosis and peripheral neuropathy
47
Q

What antibodies are present in Sjogren syndrome?

A

Antibodies to Ribonucleoproteins SS-A and SS-B (not specific)

48
Q

What neoplasm is associated with Sjogren syndrome?

A

Increased risk of lymphoma (typically marginal zone lymphoma). About 5% of patients with Sjogren syndrome develop lymphoma.

49
Q

How do you diagnose Sjogen syndrome?

A
  • Clinical findings
  • Clinical tests for tear production, tear clearance, conjunctival damage
  • Measure meant of antibodies to Ribonucleoproteins SS-A and SS-B
  • Lip biopsy (to assess minor salivary gland inflammation)
50
Q

What is systemic sclerosis (scleroderma)?

A

Chronic disease characterized by chronic inflammation, autoimmune in nature, widespread damage to small blood vessels and progressive interstitial and perivascular fibrosis of the skin and multiple organs.

51
Q

What is diffuse scleroderma?

A

Widespread skin involvement at onset, with rapid progression and early visceral involvement

52
Q

What is limited scleroderma?

A

Skin involvement is confined to the fingers, forearms and face, with late visceral involvement (more indolent form). Some patients with this form develop the CREST syndrome.

53
Q

What is CREST syndrome? (EXAM!!!)

A

Can develop in patients with limited scleroderma.
-Calcinosis (calcium deposits in soft tissue), raynaud’s phenomenon, esophageal dysmotility, sclerodactyly (thickening/tightness of skin on fingers) and telangiectasia (spider veins)

54
Q

What antibodies are seen in scleroderma?

A

Antibodies to SCL-70 (DNA Topoisomerase I); patients with CREST syndrome may have anti-centromere antibodies

55
Q

What is the pathogenesis of systemic sclerosis (scleroderma)?

A

Cause is unknown.

  • May be related to abnormal autoimmune response by CD4+ T lymphocytes to an unknown antigen(s) with release o cytokines that activate inflammatory cells and fibroblasts. -Formation of autoantibodies involved
  • Small vessel (microvascular) damage is present along with ischemic damage, progressive fibrosis
56
Q

What clinical and pathologic findings are seen in skin, GI tract, lungs and musculoskeletal system of scleroderma?

A

Raynaud’s phenomenon (most common first complaint)

  • Skin: sclerotic atrophy and sclerosis (sclerodactyly), beginning in the distal fingers and extending proximally; these changes can also involve the face; extensive dystrophic calcification in the subcutaneous fat can also be present
  • GI tract: involved in 90% of patients’ esophageal fibrosis results in dysmotility with dysphagia and reflux; small bowel involvement can result in loss of villi and dysmotility with malabsorption, cramps and diarrhea.
  • Lungs: Interstitial fibrosis (resp. failure is the most common cause of death)
  • MS system: non-destructive arthritis; 10% of patients can develop an inflammatory myositis indistinguishable from polymyositis
57
Q

What is dermatomyositis?

A
  • Autoimmune disease with immunologic injury and damage to small blood vessels and capillaries in the skeletal muscle, along with skin involvement and characteristic skin rash.
  • Muscle biopsy shows lymphocytic inflammation around small blood vessels and in the perimysial connective tissue, along with perifascicular myocyte atrophy secondary to ischemia
  • Necrotic muscle fibers with regeneration can also be seen
  • Activated B and T cells and antibodies with compliment activation are involved in the capillary damage
58
Q

What are the clinical manifestation of dermatomyositis?

A 
Muscle weakness (proximal muscle first, symmetric, with myalgia), skin rash (discoloration of upper eyelids associated with periorbital edema, accompanied by scaling erythrmatous eruption or dusky red patches over knuckles, elbows and knees)
-Extramuscular manifestations: interstitial lung disease, dysphasia secondary to involvement of oropharyngeal and esophageal muscles, myocarditis
59
Q

What should you always do in dermatomyositis?

A

CT/X-ray because 15-25 % of patients with dermatomyositis have an underlying malignancy (screen newly diagnosed patients for malignancy!)

60
Q

What is the juvenile form of dermatomyositis like?

A

Often accompanied by abdominal pain and involvement of the GI tract.

61
Q

What is Polymyositis?

A

Muscle & systemic involvement similar to that seen in dermatomyositis, except no skin involvement.
-Mostly seen in adults

62
Q

What autoantibodies are present in polymyositis?

A

Anti-Jo1 –> directed against histidyl t-RNA synthetase

63
Q

What should you treat patients with elevated creatinine kinase with (if they have polymyositis or dermatomyositis)?

A

Immunosuppresive agents

64
Q

What is the pathogenesis behind Polymyositis?

A
  • Caused by immunologic injury to muscle by activated CD8+ cytotoxic T cells.
  • Muscle biopsy shows lymphocytic inflammation surrounding and invading muscle fibers, without perifascicular atrophy seen in dermatomyositis.
  • Necrotic and regenerating muscle fibers are found throughout fascicle
  • No vascular injury seen
65
Q

What is secondary sjogren syndrome?

A

Sjogren syndrome associated with:

  • Systemic Lupus Erythematosis (SLE)
  • Rheumatoid arthritis (RA)
  • Systemic sclerosis (scleroderma)
  • Polymyositis
  • Dermatomyositis
66
Q

What is Mixed Connective tissue Disease (MCTD)?

A

Defined by the overlap features and the presence of the distinctive anti-U1-RNP antibody.
-Some patients present with an “overlap” autoimmune disease that has features that are a mixture of the features seen in SLE, systemic sclerosis, and polymyositis. These patients also have antibodies to a ribonucleoprotein particle containing U1 ribonucleoprotein (RNP)

67
Q

What antibodies are associated with RA?

A

Cyclic Citrullinated Peptide Antibodies, IgG, Serum

68
Q

What antibodies are present in Lupus Erythematous (LE)?

A
  1. Antinuclear antibodies (ANA), Serum
  2. RIB/Ribosome P Antibodies, IgG, Serum (LE + CNS involvement)
  3. CATU/Centromere Antibodies, IgG, Serum (CREST Syndrome)
  4. ENAE/Antibody to Extractable Nuclear Antigen Evaluation, Serum –> Positive for Sm = Supports LE
  5. ADNA/DNA double-stranded (ds-DNA) Antibodies, IgG, Serum (Positive supports LE)
69
Q

What antibodies are present in Sjogren syndrome or other CTD?

A
  1. ANA (antinuclear antibodies), Serum
  2. ENAE/Antibody to Extractable Nuclear Antigen Evaluation, Serum —> Positive for SS-A/Ro Antibodies or SS-B/La Antibodies
70
Q

What antibodies are present in Mixed Connective tissue disease?

A
  1. ANA (antinuclear antibodies), Serum

2. ENAE/Antibody to Extractable Nuclear Antigen Evaluation, Serum —> Positive for RNP Antibodies

71
Q

What antibodies are present in scleroderma?

A
  1. ANA (antinuclear antibodies), Serum

2. ENAE/Antibody to Extractable Nuclear Antigen Evaluation, Serum —> Positive for Scl 70 Antibodies

72
Q

What antibodies are present in polymyositis?

A
  1. ANA (antinuclear antibodies), Serum

2. ENAE/Antibody to Extractable Nuclear Antigen Evaluation, Serum —> Positive for Jo 1 Antibodies

73
Q

What clinical features are associated with DiGeorge Syndrome?

A
  • Hypoparathyroidism (tetany); absent thymic shadow on radiograph; PCP
  • Danger of GVH reaction
74
Q

What clinical features are associated with Severe Combined Immunodeficiency (SCID)?

A
  • Defective CMI (cell mediated immunity)
  • Dec. immunoglobulins
  • Treatment: Gene therapy, bone marrow transplant (patients with SCID do not reject allografts!)
75
Q

What clinical features are associated with Wiskott-Aldrich syndrome?

A
  • Symptom triad: eczema, thrombocytopenia, SP infections (pseudomonas)
  • Associated risk of malignant lymphoma
  • Defective CMI (cell mediated immunity)
  • Dec. IgM, normal IgG, Inc. IgA and IgE
76
Q

What clinical features are associated with Ataxia-telangiectasia?

A
  • Cerebellar ataxia, telangiectasias of eyes and skin
  • Inc. risk of lymphoma and/or leukemia’ adenocarcinoma
  • Inc. serum alpha-fetoprotein
  • Dec. IgA 50-80%, Dec. IgE, IgM low molecular weight variety, Dec. IgG2 or total IgG; Dec. T cell function

IHO Week 5 (7 decks)

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