Using just a few sentences, define autoimmune disease and state the key underlying immune defect.
Autoimmune diseases are immune-mediated inflammatory diseases in which the tissue and cell injury are due to immune reactions to self-antigens
***presence of autoantibodies does not always indicate the presence of autoimmune disease, as innocuous autoantibodies can be found in healthy individuals.
Autoimmunity results from the loss of self-tolerance. Self-tolerance refers to the phenomenon of unresponsiveness to an antigen as a result of exposure of lymphocytes to that antigen. Mechanisms of self-tolerance include:
a) Killing (or rendering harmless) of immature self-reactive T- and B-lymphocyte clones that recognize self-antigens in the central lymphoid organs (bone marrow, thymus) aka central tolerance.
b) In the peripheral lymphoid tissues, mechanisms of self-tolerance include anergy (irreversible functional inactivation of lymphocytes), suppression by regulatory T cells, and deletion by activation-induced cell death; as these mechanisms occur in the peripheral lymphoid tissue, this is known as peripheral tolerance
State the two key factors that combined together lead to autoimmune disease. Describe some of the ways that infections can cause autoimmunity
GENETIC SUSCEPTIBILITY→ greatest association is w/ HLA genes, but does not necessarily indicate cause/get disease
ENVIRONMENTAL TRIGGER→ associated with infections, and clinical flare-ups can be preceded by infectious prodromes. Infections may up-regulate the expression of co-stimulators on 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. In some infections, the offending organism may express antigens that have the same amino acid sequences of self-antigens. This can result in an immune response to the self-antigens, and the process is known as molecular mimicry (e.g. rheumatic heart disease, in which antibodies against streptococcal proteins cross react with myocardial proteins producing myocarditis). Some viruses, such as EBV and HIV, cause polyclonal B-cell activation, which may result in the production of autoantibodies. Another mechanism would include tissue injury due to the infection, which may release self-antigens and structurally alter self-antigens so that they are able to activate T lymphocytes
In one sentence, describe the typical clinical course of untreated autoimmune disease.
Autoimmune diseases, once initiated, tend to be progressive. While there may be sporadic relapses and remissions, there is usually inexorable tissue damage if untreated.
Describe the underlying pathologic mechanism of systemic lupus erythematosis (SLE).
Multisystem autoimmune disorder characterized by the formation of multiple autoantibodies, particularly antinuclear antibodies that result in widespread multi-organ tissue injury.
→patients with SLE can have antibodies directed against red cells, platelets, and lymphocytes, resulting in cytopenias
***fundamental defect in SLE = failure of mechanisms to maintain self-tolerance
State the potential complication of the presence of anti-phospholipid antibodies in SLE.
Pts can have Anti-phospholipid antibodies that may produce a false positive syphilis test, and can prolong the partial thromboplastin time (lupus anticoagulant). Despite having in vitro anticoagulant activity, anti-phospholipid antibodies are associated with complications of a hypercoagulable state, and patients can get venous and arterial thrombosis, resulting in spontaneous miscarriages and cerebral ischemia (this is called secondary anti-phospholipid antibody syndrome, as it is occurring in association with SLE, another autoimmune disease).
- Explain why SLE can involve multiple organ systems. Describe some of the key pathologic and clinical features seen in SLE when involving the skin, kidney, joints, and hematologic system.
Acute necrotizing vasculitis: can affect virtually any organ (CNS infarct).
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.
Skin: typically immune complex deposition at the dermoepidermal junction.
Joints: non-erosive, non-deforming small joint involvement (in contrast to RA).
Cardiovascular: fibrinous pericarditis, non-bacterial verrucous endocarditis; accelerated coronary atherosclerosis in long-term disease.
Spleen: splenomegaly.
Lungs: pleuritis, pleural effusion, interstitial fibrosis.
Mnemonics for clinical findings:
SOAP BRAIN MD:
Serositis
Oral ulcers
ARTHRITIS
PHOTOSENSITIVTY
Blood
Renal
Antinuclear antibodies
Immune
Nephritis
MALAR RASH [BUTTERFLY RASH]
DISCOID RASH
***screen test for SLE is antinuclear antibodies [3-4% of disease free individuals test positive for ANA]
Describe the underlying pathologic mechanism in rheumatoid arthritis. Describe the pathologic findings seen in the involved joints and in rheumatoid nodules.
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder that may affect many tissues and organs, but primarily attacks the joints, producing a nonsuppurative, proliferative, and inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis (stiffening or immobillity) of the joints.
Pathogenesis is uncertain, but RA is 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. The initial acute arthritis thus leads to a continuing autoimmune reaction, with activation of CD4+ helper T-cells, and the release of inflammatory mediators and cytokines that ultimately destroy the joint.
Genetic susceptibility is a major contributor to the disease, with specific HLA alleles and other genes linked to the risk of developing RA (e.g. HLA-DRB1, PTPN22).
The environmental arthritogen(s) are unknown, but may be antigens from infectious organisms. Citrullinated proteins (proteins modified by the enzymatic conversion of arginine to citrulline) formed in the body (especially in the lungs of smokers) have also been implicated as a potential autoantigen.
Immunopathogenesis of RA: Citrullinated proteins are also implicated as an autoantigen. CD4+ T cells play a key role in the autoimmune reaction, which results in the formation of a pannus (mass of inflamed synovium) which grows over the joint cartilage and results in inflammatory destruction of the joint. Autoantibodies include rheumatoid factor (typically IgM autoantibody to Fc portion of IgG) and antibodies to citrulline-modified peptides (anti-cyclic citrullinated peptide antibodies, ACCP). Rheumatoid factor is not specific for RA, as it can be seen in 1-5% of healthy people. ACCP antibodies appear to be more specific for RA.
HUMIRA: antibody to TNF
***macrophage activation releases TNF so they developed this antibody
**characteristic pathologic sign of synovium w/ RA = LOTS of plasma cells!!!
**rheumatoid nodules have palisading macrophages & inflammatory cells
Describe the underlying pathogenesis of Sjogren syndrome, and describe the typical pathologic and clinical findings. State the type of neoplasm that can be seen in Sjogren syndrome.
Chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), resulting from immunologically mediated destruction of the lacrimal and salivary glands.
• isolated disease OR in association with another autoimmune disease (e.g. rheumatoid arthritis (most common),
• typically in middle age women.
Pathogenesis is unknown, but thought to be related to aberrant T and B cell activation.
• see lymphocytic inflammation and fibrosis of lacrimal and salivary glands; may see parotid gland enlargement (Mikulicz syndrome).
• characteristically have antibodies to SS-A and SS-B (not specific).
Diagnosis of Sjogren syndrome involves clinical findings as well as clinical tests of tear production, tear clearance, and conjunctival damage; measurement of the above antibodies and lip biopsy (to assess minor salivary gland inflammation) are also used.
Increased risk for development of lymphoma (marginal zone lymphoma OR MALT).
Describe the underlying pathogenesis of systemic sclerosis (scleroderma), and describe the typical clinical and pathologic findings as seen in the skin, GI tract, lungs, and musculoskeletal system. Compare and contrast diffuse vs. limited scleroderma, and define the CREST syndrome.
Pathologic findings: chronic inflammation, presumably autoimmune in nature, with widespread damage to small blood vessels and progressive interstitial and perivascular fibrosis of the skin and multiple organs. The disease occurs in adults, with a 3:1 F:M ratio. The skin is most commonly affected, but the GI tract, kidneys, heart, muscles, and lungs are also frequently involved.
2 subtypes have been described:
A) Diffuse scleroderma: widespread skin involvement at onset, with rapid progression and early visceral involvement.
B) Limited scleroderma: skin involvement is confined to the fingers, forearms, and face, with late visceral involvement (more indolent form). Some patients with the limited form develop the CREST syndrome (calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly (skin thickening), & telangiectasia).
Cause is unknown, but may be related to an abnormal immune response by CD4+ T lymphocytes to an unknown antigen(s) with release of cytokines that activate inflammatory cells and fibroblasts. Inappropriate humoral immunity (in the form of autoantibodies) is also involved. Small vessel (microvascular) damage is also consistently present. Pathologic findings are secondary to ischemic damage and fibrosis in the affected organs.
Patients may have antibodies to Scl-70 (DNA topoisomerase 1); most patients with CREST syndrome will have anti-centromere antibodies.
Clinical findings:
• Raynaud’s phenomenon (most common initial complaint)→vasospastic response to cold or emotional stress
• Skin: sclerotic atrophy and sclerosis [fibrosis], beginning in the distal fingers and extending proximally; 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 (respiratory failure is the most common cause of death).
• Musculoskeletal system: non-destructive arthritis; 10% of patients can develop an inflammatory myositis indistinguishable from polymyositis.
• Kidneys: vascular thickening; patients may develop hypertension
Dermatomyositis:
- Inflammatory disorder of skin and skeletal muscle.
- Classic rash is violaceous discoloration of upper eyelids associated with periorbital edema, accompanied by scaling erythematous eruption or dusky red patches over the knuckles, elbows, and knees.
- Muscle weakness typically affects proximal muscles first and is symmetric, often accompanied by myalgias.
- Extramuscular manifestations may be present such as interstitial lung disease, vasculitis, and myocarditis; 20-25% of patients with dermatomyositis have an underlying malignancy!
- Juvenile form of the disease exists, accompanied by abdominal pain and involvement of the GI tract.
- Pathogenesis is thought to be related to immunologic injury to small BVs and capillaries in the skeletal muscle, perhaps secondary to autoantibodies, as well as activation of T lymphocytes. Muscle biopsy shows lymphocytic inflammation around small blood vessels & in the perimysial connective tissue, along with perifascicular myocyte atrophy. Necrotic muscle fibers with regeneration is also seen.
- Treat with immunosuppressive agents.
Polymyositis:
- Muscle and systemic involvement is similar to that seen in dermatomyositis, except for the lack of skin involvement. Mainly occurs in adults.
- Pathogenesis may be caused by T-cell mediated injury of myocytes, as well as by autoantibodies (Jo 1 antibodies (histidyl transfer RNA synthetase), which can also be seen in dermatomyositis). Muscle biopsy shows lymphocytic inflammation surrounding and invading muscle fibers, without the perifascicular atrophy seen in dermatomyositis. Necrotic and regenerating muscle fibers are found throughout the fascicle. No vascular injury is seen.
- Treat with immunosuppressive agents.
Secondary Sjogren syndrome
(Sjogren associated with one of the above diseases).
Some patients present with an “overlap” autoimmune disease w/ features that are a mixture of the features seen in SLE, systemic sclerosis, and polymyositis. These patients also have antibodies to a ribonucleoprotein (RNP) particle containing U1 ribonucleoprotein.
Mixed connective tissue disease (MCTD)
is defined by the overlap features and the presence of the distinctive anti-U1-RNP antibody.
For all of the autoimmune diseases discussed, state the key autoantibodies that are present (study the Mayo Clinic Connective Tissue Disease Cascade).
See Handout
Describe the difference between primary and secondary immunodeficiencies. In what patient population does one typically encounter primary immunodeficiencies?
- Primary immunodeficiencies [almost all genetically determined→born w/] can affect either the T or B cell functions in adaptive immunity, or the defense mechanisms in innate immunity (e.g. phagocytic function or complement system). Most primary immunodeficiency states manifest themselves in infancy, between 6 months and 2 years of life, and they are detected as a result of multiple recurrent infections.
→B cell and combined B and T cell abnormalities account for nearly three-fourths of the primary immunodeficiencies; isolated T cell, phagocytic, and complement defects are rare. - Secondary (due to complications of cancer, infection, malnutrition, immunosuppression, irradiation, or chemo)
MUCH MORE COMMON THEN 1’
Describe the underlying pathogenic defect (and pertinent genetics if appropriate), as well as the findings of appropriate laboratory tests (e.g. immunoglobulin levels, blood smear for CHS, complement tests).
page 5
Complement deficiency syndromes:
- Hereditary deficiencies have been described for virtually all components and several pathway regulators.
- Deficiencies of the early classical pathway components (C2, C1, C4) show little or no increase in susceptibility to infections, but there is an increased incidence of an SLE-like autoimmune disease.
- Deficiency of components of the alternate pathway (properdin and factor D) are rare and are associated with recurrent pyogenic infections.
- Deficiency of C3 affects both the classical and alternative pathways, and results in susceptibility to serious and recurrent pyogenic infections. C3 deficiency also results in increased incidence of immune complex-mediated glomerulonephritis.
- Deficiencies of the terminal components (C5, C6, C7, C8, C9) show increased susceptibility for recurrent neisserial (gonococcal and meningococcal) infections. This is due to impaired function of the MAC involved in the lysis of organisms (Neisseria bac have thin walls; are especially sensitive to the lytic actions of complement).
• Chédiak-Higashi syndrome:
o Rare autosomal recessive disorder characterized by recurrent pyogenic infections, partial oculocutaneous albinism, progressive neurologic abnormalities, and mild coagulation defects.
o The gene responsible for this defect is called CHS1/LYST, and is a trafficking regulatory protein. This results in defective fusion of phagosomes and lysosomes in phagocytes, causing susceptibility to infections.
o The diagnosis of CHS can be made by examination of a peripheral smear for pathognomonic giant cytoplasmic granules in leukocytes and platelets, and confirmed with genetic testing.
o Treatment of choice = Hematopoietic cell transplantation (HCT)
List the causes of secondary immunodeficiency. State which type of infection patients without a spleen are at risk for and why.
Causes of secondary immune deficiency:
-Malignancy (disease-related immunosuppression):
Hodgkins disease, CLL (e.g. hypogammaglobulinemia in chronic lymphocytic leukemia)
Multiple myeloma
Malignancy of solid tumors (tumor-derived immunosuppressive factors)
-Disorders of biochemical homeostasis:
*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. Worldwide, malnutrition is the most common cause of acquired immunodeficiency)
-Autoimmune disease (e.g. SLE, RA)
-Severe burn injury
-Exposure to radiation, toxic chemicals
-Asplenia/hyposplenism (loss of splenic macrophages post splenectomy can lead to increased risk of bacterial infection with encapsulated organisms, particularly with Streptococcus pneumoniae; as such, these patients receive vaccinations for S. pneumoniae, H. influenzae, and N. meningitidis)
-Aging
List the three ways that one could suspect a patient has an immunodeficiency.
o 1. Clinical history indicates that the patient has an immunodeficiency
o 2. Patient presents with opportunistic infection from a “signature organism” (i.e. Pneumocytosis jiroveci, oral candidiasis, invasive aspergillus)
o 3. Patient presents with recurrent infections or other symptoms that are suggestive
• CBC with diff
: to assess for decrease in lymphocytes (lymphopenia) and/or decrease in neutrophils (neutropenia).
• Comprehensive metabolic panel
to assess for diabetes, kidney or liver disease
• Sedimentation rate, CRP
to assess for inflammatory state (infection, autoimmune disease)
o Antibody deficiencies
(B-cell function): immunoglobulin levels.
