Systemic Autoimmune Diseases & Immunodeficiencies - Nelson

Question 1

What are autoimmune diseases?

Answer 1

Immune-mediated inflammatory disease in which tissue and cell injury are due to immune reactions to self-antigens (autoimmunity).

• May be mediated by:
  
  • autoantibodies
  • immune complexes
  • T-lymphocytes.

Question 2

What is the key underlying immune defect in autoimmune diseases?

Answer 2

loss of self-tolerance

(phenomenon of unresponsiveness to an individual’s own antigens)

Question 3

Does the presence of autoantibodies always indicate the presence of autoimmune disease?

Answer 3

NO

Presence of autoantibodies does not always indicate the presence of autoimmune disease.

Question 4

What are the two key factors that combined lead to autoimmune disease?

Answer 4

• Inheritance of susceptible genes
  
  • interfere with self-tolerance
• Environmental triggers
  
  • infections
  • tissue injury
  • inflammation
  • activation of self-reactive lymphocytes

Question 5

What are some of the ways that infections can cause autoimmunity?

Answer 5

• Up-regulate the expression of co-stimulators on APC’s
• Molecular Mimicry
  
  • offending organism expresses antigens that have the same amino acid sequence of self-antigens
• Viruses (EBV, HIV) - cause polyclonal B-Lymphocyte activation
• Tissue injury due to the infection releases self-antigens
  
  • structurally alter self-antigens
• Hygiene Hypothesis
  
  • as infections become better controlled, autoimmune diseases are increasing

Question 6

What is the typical clinical course of untreated autoimmune disease?

Answer 6

• Initially may be directed at a specific organ or tissue
  
  • resulting in organ specific disease
• May become directed at widespread antigens
  
  • resulting in systemic or generalized disease; tend to be progressive.

Question 7

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

Answer 7

• Fundamental defect: failure of mechanisms to maintain self-tolerance.
  
  • pathogenesis related to presence of susceptibility genes + environmental triggers (UV light, estrogen, certain medications)
• formation of multiple autoantibodies (anti-nuclear antibodies or ANA’s)
  
  • cause injury by depositing immune complexes
  • bind antibodies to various cells and tissues

Question 8

What is the potential complication of the presence of anti-phospholipid antibodies in SLE?

Answer 8

• May produce a false positive syphilis test
• Can prolong the partial thromboplastin time (lupus anticoagulant)
• Secondary Anti-phospholipid Antibody Syndrome:
  
  • Hypercoagulable state
  • Venous and arterial thrombosis
  • Spontaneous miscarriages
  • Cerebral ischemia

Question 9

Why can SLE involve multiple organ systems?

Answer 9

• Most of the systemic lesions of SLE are caused by immune complex deposition
  
  • Type III Hypersensitivity
• Loss of self-tolerance and persistence of nuclear antigens leads to the formation of antigen-antibody complexes
  
  • deposited in the tissues → injury

Question 10

What are some of the key pathologic and clinical features seen in SLE when involving the skin, kidney, joints, and hematologic system?

Answer 10

• Skin: Erythema in light exposed areas, IC deposition at dermoepidermal junctions
• Kidney: IC deposition in glomeruli, tubular or peritubular capillary basement membrane, or larger blood vessels
• Joints: non-erosive, non-deforming small joint involvement
• Hematologic: Hemolytic anemia with reticulocytosis or leukopenia/lymphopenia/thrombocytopenia
• Cardiovascular: Fibrinous pericarditis, non-bacterial endocarditis, accelerated coronary atherosclerosis in long-term disease
• Lungs: Pleuritis, pleural effusion, interstitial fibrosis

Question 11

What does the mnemonic “SOAP BRAIN MD” stand for in terms of the pathologic findings in SLE?

Answer 11

• Serositis
• Oral Ulcers
• Arthritis
• Photosensitivity, Pulmonary Fibrosis
• Blood Cells
• Renal, Raynauds
• ANA
• Immunologic (Anti-Sm, Anti-dsDNA)
• Neuropsych
• Malar Rash
• Discoid Rash

Question 12

What is the underlying pathologic mechanism in rheumatoid arthritis?

Answer 12

• triggered by exposure to an arthitogenic (arthritis causing) antigen in a genetically predisposed individual
  
  • results in breakdown of immunological self-tolerance & chronic inflammatory reaction

Question 13

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

Answer 13

• Joints:
  
  • non-suppurative proliferative and inflammatory synovitis
  • pannus formation: mass of inflamed synovium
  • Marked chronic papillary synovitis
  • dense chronic inflammatory infiltrate rich in plasma cells
  • inflammatory destruction of the articular cartilage and ankylosis
• Nodule:
  
  • Central fibrinoid necrosis surrounded by palisade of macrophages and scattered chronic inflammatory cells

Question 14

What are the typical pathological findings in Sjogren Syndrome?

Answer 14

• lymphocytic inflammation involving lacrimal and salivary glands
• followed by fibrosis and gland atrophy as the disease develops
• may also see parotid gland enlargement

Question 15

What are the typical pathologic and clinical findings in Sjogren Syndrome?

Answer 15

• dry eyes (keratoconjunctivitis sicca)
• dry mouth (xerostomia)
  
  • resulting from autoimmune immunologically mediated destruction of lacrimal and salivary glands
• common in middle aged women
• some patients will also exhibit extraglandular disease:
  
  • synovitis
  • pulmonary fibrosis
  • peripheral neuropathy

Question 16

What is the underlying pathogenesis of Sjogren syndrome?

Answer 16

• Unknown
• Thought to be related to aberrant T and B cell activation in genetically susceptible individulas
  
  • possible trigger infection of salivary glands

Question 17

What is the underlying pathogenesis of systemic sclerosis (scleroderma)?

Answer 17

• Unknown
• May be related to abnormal, autoimmune response by CD4+ T lymphocytes to an unknown antigen(s)
  
  • release of cytokines that activate inflammatory cells and fibroblasts
• Inappropriate humoral immunity
  
  • autoantibodies

Question 18

What are the typical clinical findings in Systemic Sclerosis (Scleroderma) as seen in the skin, GI tract, lungs, and musculoskeletal system?

Answer 18

• Clinical:
  
  • Raynaud’s phenomenon
  • Skin: sclerotic atrophy & sclerosis, fingers→proximally/face, dystrophic calcification in the subQ fat
  • GI: esophageal fibrosis→dysmotility, dysphagia & reflux, loss of villi with malabsorption, cramps, and diarrhea (90% of patients)
  • Lungs: interstitial fibrosis
  • MSK: non-destructive arthritis, inflammatory myositis (10%)

Question 19

What are the typical pathologic findings in Systemic Sclerosis (Scleroderma) as seen in the skin, GI tract, lungs, and musculoskeletal system?

Answer 19

• Pathologic:
  
  • small vessel (microvascular) damage
  • ischemic damage
  • progressive fibrosis
  • antibodies to Scl-70 (DNA topoisomerase)

Question 20

What is the underlying pathogenic defect (and pertinent genetics if appropriate) in X-linked Agammaglobulinemia (Bruton’s Aggammaglobulinemia)?

Answer 20

• Failure of B-Cell precursors (Pro-B and Pre-B cells) to develop into mature B-cells; maturational defect due to X-linked mutation which codes for cytoplasmic Bruton tyrosine kinase (Btk)
• X-linked - seen almost entirely in males

Question 21

What are the laboratory test findings in X-linked Agammaglobulinemia (Bruton’s Aggammaglobulinemia)?

Answer 21

• Decreased or absent B cells in peripheral blood
• decreased/absent Ig
• no plasma cells
• underdeveloped germinal centers

Question 22

What is the underlying pathogenic defect (and pertinent genetics if appropriate) in Common Variable Immunodeficiency?

Answer 22

• Heterogenous group of disorders characterized by failure of B cells to differentiate into plasma cells
• Sporadic and inherited forms of disease, both sexes affected equally, symptoms later onset in childhood or adolescence/young adults
• Increased risk of Lymphomas and gastric cancers

Question 23

What are the laboratory test findings in Common Variable Immunodeficiency?

Answer 23

• Decreased Ig production (hypogammaglobulinemia)
• Normal numbers of B cells in blood
• B cell lymphoid areas (germinal centers) are hyperplastic

Question 24

What is the underlying pathogenic defect (and pertinent genetics if appropriate) in Isolated IgA Deficiency?

Answer 24

• European descent; sinopulmonary infections and diarrhea; commonly also have deficiency of IgG2 and IgG4
  
  • respiratory tract allergies
• Failure of B-Cells to differentiate into IgA producing cells

Question 25

What are the laboratory test findings in IgA Deficiency?

Answer 25

• low serum and secretory IgA levels
• Increased risk of AI disease, anaphylactic reactions to blood transfusions

Question 26

What is the underlying pathogenic defect (and pertinent genetics if appropriate) in DiGeorge Syndrome (Thymic Hypoplasia)?

Answer 26

• T cell deficiency due to failure of development of the 3rd and 4th pharyngeal pouches
  
  • Normally give rise to thymus
  • Variable loss of T-cell mediated immunity (lack of thymus)
• Tetany (lack of parathyroid glands)
• Congenital defects of heart and great vessels and facial abnormalities
• Not familial, due to sporadic deletion of a gene on chromosome 22q11

Question 27

What are the laboratory test findings in DiGeorge Syndrome (Thymic Hypoplasia)?

Answer 27

• Low levels of T-Cells in peripheral blood, T-cells in lymph nodes and spleen depleted
• Present with fungal, viral, Pneumocystis jiroveci infections

Question 28

What is the underlying pathogenic defect (and pertinent genetics if appropriate) in Hyper-IgM Syndrome?

Answer 28

• 70% of individuals have X-linked recessive mutations in the gene encoding CD40 ligand → can’t deliver class-switching signal
• Pyogenic infections (low levels of opsonizing IgG)
• Patients are able to make IgM, but are deficient in their ability to make IgG, IgA, and IgE antibodies (defect in immunoglobulin class switching)

Question 29

What are the laboratory test findings in Hyper-IgM Syndrome?

Answer 29

• normal IgM levels, little IgG, no IgA or IgE

Question 30

What is the underlying pathogenic defect (and pertinent genetics if appropriate) in Severe Combined Immunodeficiency (SCID)?

Answer 30

• Profound defects of both humoral and cell-mediated immunity; without hematopoietic cell transplantation, death occurs within a year.
• Many different genetic lesions can cause SCID
• Autosomal Recessive Disorder
• Most common form (50-60%) is X-linked

Question 31

What are the laboratory test findings in Severe Combined Immunodeficiency (SCID)?

Answer 31

• Reduced cytokine signaling and T cell development is markedly impaired
• T cells and NK cells are decreased and Ab synthesis is severely impaired due to lack of T helper cells

Question 32

What is the underlying pathogenic defect (and pertinent genetics if appropriate) in Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome)?

Answer 32

• X-Linked Recessive Disorder with Thrombocytopenia, eczema, vulnerability to recurrent infection
• Mutations in gene encoding Wiskott-Aldrich syndrome protein (WASP) located on short arm of x-chromosome
  
  • Believed to link cell membrane receptors, including antigen receptors
  • Defects in cell migration and signal transduction

Depletion in T-Cells with variable loss of cell-mediated immunity

Question 33

What are the laboratory test findings in Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome)?

Answer 33

• Depletion in T-Cells with variable loss of cell-mediated immunity
  
  • Antibody production to polysaccharide antigens is absent with low levels of serum IgM
  • IgG normal, IgA and IgE elevated

Question 34

What are the laboratory test findings in X-linked Lymphoproliferative Syndrome?

Answer 34

• decreased antibody responses to antigens (particularly to EBV nuclear antigen)
• impaired T-cell proliferative responses to mitogens
• decreased NK-cell function
• inverted CD4:CD8 ratio.
• Some survivors of EBV infection have hypogammaglobulinemia.
• A bone marrow biopsy can help confirm HLH.

Question 35

What is the underlying pathogenic defect (and pertinent genetics if appropriate) in X-linked Lymphoproliferative Syndrome?

Answer 35

• Inability to eliminate EBV → severe and sometimes fatal infectious mononucleosis and B cell lymphomas
• Most cases due to mutations in gene encoding a mlc called SLAM-associated protein (involved in activation of NK cells and T and B cells)

Question 36

What are the causes of secondary immunodeficiency?

Answer 36

• Another underlying disorder
  
  • Immunosuppressive therapy
    
    • cytotoxic therapy for malignancy
    • treatment of autoimmune disease
    • bone marrow ablation prior to transplantation
    • treatment/prophylaxis of GVHD
    • treatment or rejection following solid organ transplant
  • Asplenia/hypospenism
  • Microbial infection (e.g. HIV/AIDS)
    
    • loss of CD4+ T helper lymphocytes
  • Malignancy
    
    • Hodgkins disease, CLL
    • Multiple Myeloma
    • Malignancy of solid tumors
  • Disorders of biochemical homeostasis:
    
    • diabetes
    • renal insufficiency/dialysis
    • hepatic insufficiency/cirrhosis
    • malnutrition
  • Autoimmune disease
  • Severe burn injury
  • Exposure to radiation, toxic chemicals
  • Aging

Question 37

Which type of infection are patients without a spleen at risk for? WHY?

Answer 37

• Bacterial infection with encapsulated organisms
  
  • Streptococcus pneumoniae
• VACCINATE
  
  • S. pneumoniae
  • H. influenzae

Question 38

What are the three ways that one could suspect a patient has an immunodeficiency?

Answer 38

• Clinical History
  
  • known primary immunodeficiency
  • consider causes of secondary immunodeficiency
• Opportunisitic Infection from a Signature Organism
  
  • e.g. pneumonia due to Pneumocystis jiroveci
  • e.g. Nocardia
• Repeated Infections

Question 39

What laboratory tests would you order to assess B-cell function, T-cell function, phagocytic function, and complement?

Answer 39

• B-Cell Function
  
  • Immunoglobulin levels to assess for antibody deficiencies
• T-Cell Function
  
  • Flow Cytometry for cellular immunity
• Phagocytic Function
  
  • CBC, Peripheral blood smear, genetic tests, test neutrophil function
• Complement Function
  
  • Total serum complement (CD50)