Autoimmunity Flashcards
Type II Autoimmune disorder
Damage primarily mediated by autoantibodies against host cell surfaces or extracellular matrix; activates complement or acts as receptor agonist/antagonist.
Type III Autoimmune disorder
Damage primarily mediated by autoantibodies against soluble intracellular antigens or serum antigens; immune complex deposition, complement activation, and inflammation.
Type IV Autoimmune disorder
Damage primarily mediated by auto-reactive effector T cells.
What are receptor agonist and antagonist autoantibodies?
Agonist: Stimulate receptor function upon binding (e.g., Graves’ disease).
Antagonist: Inhibit receptor function upon binding (e.g., autoimmune pernicious anemia).
Genetic factors involved in autoimmunity?
Polymorphisms in genes related to tolerance induction and T cell activation/regulation (MHC genes, cytokine/cytokine receptor genes, BCR and TCR genes, complement genes, etc.).
Specific examples include AIRE, FoxP3, Fas, and HLA/MHC haplotypes.
AIRE’s role in autoimmunity
AIRE is a transcription factor that induces the expression of tissue-specific proteins in the thymus. Defects lead to escape of self-reactive T cells from negative selection (APECED).
FoxP3’s role in autoimmunity
FoxP3 is a transcription factor required for Treg cell development. Defects can cause immune dysregulation (IPEX).
Role of Fas and FasL in autoimmunity
Fas and FasL mediate apoptosis of self-reactive T cells. Defects lead to autoimmune lymphoproliferative syndrome (ALPS)
How does MHC variability affect autoimmunity?
MHC molecules present self-antigen peptides. Certain MHC allotypes present some self-antigens more efficiently, increasing the risk of an immune response (e.g., HLA-B27 and ankylosing spondylitis).
How do trauma and infection induce autoimmunity?
Trauma can release hidden self-antigens. Infections can activate APCs to present self-antigens, leading to self-reactive T cell activation (molecular mimicry and epitope spreading). Examples include rheumatic fever and reactive arthritis.
epitope spreading
Autoimmune response broadens over time to include additional self-antigens.
What are some examples of Type II autoimmune disorders?
Immune/autoimmune thrombocytopenic purpura (ITP or ATP), heparin-induced thrombocytopenia (HIT), acquired autoimmune hemophilia.
What is ITP/ATP?
Autoantibodies against platelet cell surface molecules (e.g., GPIIb/IIIa) lead to platelet destruction, causing thrombocytopenia, purpura, and petechiae.
If HIV status is unknown - test also presents w/ SLE
What is HIT?
Autoantibodies against heparin-PF4 complexes trigger platelet activation and destruction, leading to thrombocytopenia and thrombosis.
Heparin inhibits ATIII (ATIII inhibits factor Xa)
What is acquired autoimmune hemophilia?
Autoantibodies against coagulation factor VIII inhibit clotting, leading to prolonged bleeding times. Symptoms include spontaneous hematomas and hemarthrosis. Diagnosis involves prolonged aPTT and a mixing study showing factor VIII deficiency.
Inhibits intrinsic pathway
What is autoimmune hemolytic anemia (AIHA)?
Autoantibodies against RBCs leading to RBC destruction (intravascular or extravascular hemolysis). Types include warm (IgG) and cold (IgM) AIHA, each with distinct clinical presentations and diagnostic tests (Direct Coombs test).
What is autoimmune pure red cell aplasia?
Autoimmune destruction of erythroid precursors, leading to severe anemia with normal WBC and platelet counts. Diagnosis involves low reticulocyte count and bone marrow examination showing absence of erythroblasts.
RBCs that reach maturity are normal
What is autoimmune pernicious anemia (PA)?
Autoantibodies against intrinsic factor or parietal cells impair vitamin B12 absorption, leading to macrocytic anemia and neurological symptoms. Diagnosis involves detection of anti-IF and anti-parietal cell antibodies and low B12 levels.
What is systemic lupus erythematosus (SLE)?
Type III autoimmune disorder characterized by autoantibodies against nuclear and cytoplasmic antigens. Immune complex deposition in various tissues causes inflammation and organ damage. Diagnosis involves testing for antinuclear antibodies (ANA) and anti-dsDNA antibodies.
What is acquired aplastic anemia?
Severe bone marrow failure due to destruction of hematopoietic stem cells. Possible causes include self-reactive T cells and stem cell defects.
Symptoms include pancytopenia (anemia, neutropenia, thrombocytopenia) and bone marrow biopsy reveals hypocellular marrow.
What is celiac disease?
Type IV hypersensitivity to gluten peptides leading to small intestinal inflammation (villous atrophy) and malabsorption. Diagnosis involves serologic testing for anti-tissue transglutaminase antibodies and HLA-DQ2/DQ8 typing.
What is Crohn’s disease?
Chronic inflammatory bowel disease believed to be caused by dysregulation of immune responses to gut microbiota. Symptoms include diarrhea, abdominal pain, weight loss, and extraintestinal manifestations. Diagnosis involves endoscopy, imaging, and serologic testing.
Describe Plasmaphoresis
A procedure where plasma is removed from the blood, purified cells are combined with donor plasma or saline, and the mixture is returned to the patient. It removes circulating autoantibodies and cytokines.
Describe IVIG
Intravenous immunoglobulin; high doses of non-autoreactive IgG may prevent autoantibody/self-antigen complex formation and reduce inflammation.
What is worm therapy?
From immuno/heme block
Infection with parasitic worms to modulate the immune response, primarily used in Crohn’s disease and other autoimmune conditions. The exact mechanism is not fully understood but is thought to involve a shift towards a Th2 response.
Cold AIHA
Primarily presents with acrocyanosis (blue extremities), Raynaud’s phenomenon (coldness/numbness in extremities), and anemia.
IgM mediated
Warm AIHA
Presents primarily with symptoms of anemia (fatigue, weakness, dyspnea, pallor). Both involve autoantibodies against RBCs, but the antibody isotype (IgM vs. IgG) and temperature sensitivity differ.
What are the key diagnostic tests for AIHA?
Direct Coombs test (detects autoantibody-coated RBCs) and peripheral blood smear (to assess for hemolysis). Additional tests might include antibody identification and complement levels.
Explain the pathophysiology of autoimmune pernicious anemia (PA) in detail.
Autoantibodies target either intrinsic factor (IF) or parietal cells, impairing B12 absorption in the terminal ileum. This leads to a deficiency of B12, affecting DNA synthesis and myelin production, resulting in macrocytic anemia and neurological symptoms
What is the role of tissue transglutaminase in celiac disease?
Tissue transglutaminase (tTG) modifies gluten peptides, making them immunogenic. The modified peptides are presented (bound to gluten) to HLA-DQ2/DQ8-positive T cells, triggering an autoimmune response that damages the small intestinal mucosa.
True or False: Crohn’s disease is a classic autoimmune disease targeting self-antigens.
False
Crohn’s disease is thought to be caused by a dysregulated immune response to the gut microbiota, not a direct attack on self-antigens. It’s considered an inflammatory bowel disease with an autoimmune component.
List some extraintestinal manifestations of Crohn’s disease.
Arthritis, rash, eye inflammation, oral ulcers, and B12 deficiency (due to malabsorption).
What are some key genetic markers associated with Crohn’s disease?
NOD polymorphisms (affecting pattern recognition receptors) and HLA associations (although less strongly associated than in celiac disease). Seronegative p-ANCA and positive ASCA antibodies can help differentiate Crohn’s from ulcerative colitis.
Compare the genetic associations of Celiac Disease and Crohn’s Disease.
Celiac Disease shows a strong association with HLA-DQ2 and HLA-DQ8.
Crohn’s disease has a weaker association with HLA alleles and shows a stronger association with NOD polymorphisms.
What are some potential mechanisms by which worm therapy might help autoimmune diseases?
Induction of a Th2 response, which counteracts the inflammatory Th1/Th17 response in diseases like Crohn’s. It may also involve changes in gut microbiota composition and immunoregulation.
Explain the difference between Type I and Type II HIT
Type I HIT is a non-immune mediated, transient thrombocytopenia occurring early after heparin exposure. Type II HIT is an immune-mediated reaction, often more severe, involving antibodies against the heparin-PF4 complex, leading to platelet activation and thrombosis. Type II is far more serious.
What is the significance of the “mixing study” in diagnosing acquired hemophilia?
The mixing study mixes the patient’s plasma with normal plasma. A correction in the aPTT indicates a factor deficiency (e.g., factor VIII). No correction suggests the presence of an inhibitor (autoantibody) against the clotting factor.
How does the Direct Coombs test work, and what autoimmune conditions is it used for?
The Direct Coombs test detects the presence of antibodies or complement bound to the surface of red blood cells (RBCs). It’s used to diagnose autoimmune hemolytic anemia (AIHA) by determining if autoantibodies are attached to the patient’s red blood cells.
Contrast the typical bone marrow findings in acquired aplastic anemia versus autoimmune pure red cell aplasia (PRCA).
Acquired aplastic anemia: Shows hypocellular marrow with replacement by fat and fibrous tissue.
PRCA: Primarily reveals a near absence of erythroblasts in an otherwise normal bone marrow.
Describe the role of NETs (Neutrophil Extracellular Traps) in the pathogenesis of SLE.
Abnormal processing of NETs is hypothesized as a potential trigger for SLE. NET components, including nuclear material, are released into circulation, where they can stimulate the production of autoantibodies against nuclear antigens, leading to immune complex formation and tissue damage.
Explain how a deficiency in complement components (e.g., C1, C2, C4) might contribute to SLE development.
Deficiencies in complement components impair the clearance of immune complexes, allowing them to deposit in tissues and cause inflammation and damage. This contributes to the pathogenesis of SLE.
How does HLA typing contribute to the diagnosis and understanding of autoimmune diseases?
Certain HLA alleles are strongly associated with an increased risk for specific autoimmune diseases (e.g., HLA-B27 and ankylosing spondylitis). HLA typing helps in assessing genetic predisposition, diagnosis, and predicting disease course. It also helps define which self-antigens might be presented more efficiently leading to autoimmunity.
What are some common laboratory findings in patients with acquired aplastic anemia?
Pancytopenia (low RBCs, WBCs, and platelets)
bone marrow biopsy showing hypocellularity with increased fat and fibrous tissue
abnormal peripheral blood smear findings (e.g., macrocytosis).
Distinguish between the clinical presentations of Crohn’s disease and ulcerative colitis. What laboratory tests might help differentiate them?
Crohn’s disease can affect any part of the GI tract (transmural inflammation) and presents with more varied symptoms, including granulomas.
Ulcerative colitis typically affects the colon and rectum (mucosal inflammation).
Laboratory tests such as p-ANCA (negative in Crohn’s, positive in UC) and ASCA (positive in Crohn’s, negative in UC) may aid in the differentiation.
Which autoimmune disorders are associated with an increased risk of specific malignancies?
SLE (lymphoma)
inflammatory bowel disease (Crohn’s disease and ulcerative colitis) (colorectal cancer)
autoimmune thyroiditis (lymphoma).
How does the “bystander effect” contribute to the progression of autoimmune diseases?
In the context of autoimmunity, bystander activation refers to the non-specific activation of immune cells by inflammatory mediators released at the site of autoimmune attack. This can amplify the inflammatory response and contribute to the spread of autoimmune damage beyond the initial target tissue.
When does rheumatic fever typically present?
2-5 wks after strep infection
Which immune effector type is LEAST LIKELY to mediate an autoimmune disease (choose the SINGLE BEST answer)
A. IgM
B. IgG
C. IgE
D. CD4+ Th1 cells
C. IgE
Yes
Polymorphisms in which gene are MOST LIKELY to be associated with an autoimmune disease?
MHC class I and class II (HLA)
AIRE/FoxP3 and FasL/Fas are also associated with autoimmune disease but to a lesser extent
A. Streptococcus pyogenese throat infection and HLA-B27
B. Neisseria gonorrhoeae genital infection and HLA-DR15
C. Chlamydia trachomatis genital infection and HLA-B27
D. Mycobacterium tuberculosis lung infection and HLA-DR15
C. Chlamydia trachomatis genital infection and HLA-B27
Reactive arthritis: can’t see, can’t pee, can’t climb a tree… Reiter’s disease, also known as reactive arthritis, is a seronegative HLA-B27-associated autoimmune disease, characterised by oligoarthritis of large joints with additional ophthalmic and urological manifestations
A patient produces autoantibody against gastric parietal cells. Which are MOST LIKELY key features that will differentiate this disease from other disorders discussed in this session?
Autoimmunity lecture
Lemon-colored skin, swollen, red tongue, shuffling gait, and mental sluggishness
Also scleral icterus
A patient produces IgM autoantibody against blood group antigens. Which are MOST LIKELY key features that will differentiate this disease from other disorders discussed in this session?
Autoimmunity lecture
Persistent blue coloration of extremities and coldness/numbness of the hands and feet
Cold AIHA
A patient produces IgG autoantibody against nuclear antigens and double stranded DNA. Which are MOST LIKELY key features that will differentiate this disease from other disorders discussed in this session?
Fever, joint pain/arthritis, rash, and symptoms of acute kidney injury
Which is initially mediated by a CD4+ Th1 response against a food product?
A. Crohn’s disease
B. Reactive arthritis
C. Celiac disease
D. Rheumatic fever
E. Systemic lupus erythematosus
C. Celiac’s disease
Which would MOST LIKELY present with a reduced RBC count, a low platelet count, and increased susceptibility to infections?
Autoimmunity lecture
Acquired aplastic anemia
Which would MOST LIKELY present with a normal white cell count, a normal platelet count, but a markedly reduced RBC count?
Autoimmunity lecture
Autoimmune pure red cell aplasia
Recent onset of abnormal mucocutaneous bleeding in a postpartum woman without a history of bleeding episodes
From autoimmune lecture
Congenital hemophilia
Also presents in geriatric pop.
What mutations predispose Pt’s to SLE?
Any early complement mutation (especially C1)
HLA-DR2/3/15
A. Increased release of clotting factors
C. Increased destruction of platelets by macrophages
IgG autoAb against of combination of platelet factor IV and heparin complex causes platelets to release granules
Macrophages in spleen and liver recognize surface complex on platelets and clear them from blood
B. Crohn’s disease
Crohn’s - affects terminal ileum - reacts against normal gut flora
