BLD 434 - Quiz 6 Flashcards
Explain the immune system mechanism responsible for each of the 4 types of hypersensitivity reactions, including the isotype of the antibody involved (as appropriate) and/or effector cell types acting in each.
Type I: IgE mediated, mast cell degranulation (FceRI cross linking). Ex: asthma, hay fever
Type II: IgG response, antibody mediated cell surface rations that cause cytotoxicity, complement activation. Ex) hemolytic anemia, HDFN
Type III: IgG response immune complex mediated, complement activation Ex: arthus reaction
Type IV: cell mediated, sensitized T cells (mostly Tc (CD8) but some Th1 (CD4)), activated macrophages. Ex: contact dermatitis
Explain how an “immediate hypersensitivity” differs from a “delayed-type hypersensitivity (DTH)” response, and what type of hypersensitivity (I – IV) is being tested for by each.
Delayed response hypersensitivity reaction occurs 1-3 after contact with the antigen while immediate hypersensitivity reactions occur immediately
Immediate hypersensitivity = Type I hypersensitivity
Delayed response hypersensitivity = Type IV hypersensitivity
Identify which hypersensitivity is associated with histamine release.
Type 1
Describe the utility of total serum IgE testing, skin prick testing, and allergen-specific laboratory testing, listing the advantages and disadvantages of each.
Total serum IgE testing: RIST. Elevated total serum IgE. Advantage: inexpensive and suggests further testing Disadvantage: not sensitive and doesn’t identify allergen
Skin prick testing: Wheal reaction. Advantage: positive test is clinically significant Disadvantage: danger of systemic reaction, traumatic to the patient, and only tests limited individual allergens
Allergen-specific laboratory testing: RAST. Advantage can be taken with antihistamines and only require single skin puncture to draw blood for serum testing. Disadvantage: lower specificity than skin testing and only tells if IgE is present not if its responsible for current allergic symptoms
Identify common examples of type II hypersensitivities.
Type II hypersensitivities occur following administration of certain types of drugs and are responsible for blood transfusion reactions, HDN, some autoimmune diseases including Goodpasture’s syndrome, Grave’s disease, and myasthenia gravis.
For the following illnesses/diseases, identify the type of hypersensitivity responsible: “serum sickness”, celiac disease, poison ivy hypersensitivity, allergic asthma, food allergy such as shellfish allergy.
Serum sickness: type III hypersensitivity
Celiac disease: type IV hypersensitivity
Poison ivy hypersensitivity: Type IV hypersensitivity
Allergic asthma: Type I hypersensitivity
Food allergy such as shellfish allergy: type I hypersensitivity
Identify which hypersensitivity responses involve complement activation.
Type II and Type III hypersensitivity responses
Identify whether CD4+ T cells, CD8+ T cells, and/or B cells are responsible for autoimmune disease.
All are responsible for autoimmune disease – CD4, CD8, and B cells – Both autoimmune antibodies and T cells (Tc) have been found to be responsible for eliciting autoimmunity.
Ultimately, because of the requirement for T cell help in antibody production, all persistent autoimmunity must be due to breach in T cell tolerance – hence the link of autoimmunity to HLA genes, esp. MHC class II, but also MHC class I.
Identify two proteins involved in T lymphocyte self-tolerance that when defective in humans lead to generalized autoimmune disease.
Defects in tolerance development or maintenance itself lead to more generalize autoimmunity are AIRE and FoxP3
Define “relative risk” and the ultimate effect that it has on an individual’s likelihood to develop any given autoimmune disease. Be able to interpret a relative risk score.
Relative risk: if you have the associated HLA gene, relative risk is the increased risk you have over the general population to get the disease.
However, just because you have HLA susceptibility does not mean that you will get the disease. Divide total risk by the total risk to get the actual risk of getting the disease.
Explain the role of HLA alleles in development of autoimmunity (i.e. what are the HLA molecules doing exactly to trigger autoimmunity?).
Linked more commonly to increased susceptibility to autoimmunity to due their ability to present self-antigen
List and define/explain the mechanisms of several factors described in the textbook reading that have been proposed to be risk factors for autoimmune disease development.
- Release of sequestered antigens by tissue damage: Intracellular proteins and nucleic acids that are released by traumatic damage into extracellular fluid and elicit an inflammatory response at the same time
- Inflammation causing ectopic expression of MHC Class II on cells that would not normally express it: IFN-y can cause several types of cell types to express MHC Class II in a cell-mediated response to a virus. These cells may express a protein that is not made in the thymus and hence there is no T cell tolerance to that protein.
- Molecular mimicry: An immune response to a pathogen triggers a TCR/BCR that cross-reacts with the self-antigen. Infections causing inflammation (such as Strep A, chlamydia, Lyme disease, Coxsackie virus, etc.) can lead to molecular mimicry.
- Polyclonal B cell activation: Triggers antibody synthesis to many self-antigens. Antibodies produced are all IgM due to no T cell help.
- Inhibitory FcyR polymorphisms: A defect in the immune system itself that leads to inability to inhibit B cell responses even antibody is present in adequate amount
- Genetic mutations in C1-C4: A defect in the immune system itself that leads to C1-C4 and complement receptors that bind to C1q predispose to Lupus. This is caused from ineffective clearance of immune complexes that eventually activates complement and lyses cells and spews out proteins which are processed and presented in MHC Class II. These proteins are the target of autoimmunity in Lupus.
CHECK: Define epitope spreading (in the context of autoimmune disease) and how linked recognition is responsible for epitope spreading.
Epitope spreading is a common feature of autoimmune disease that refers to the amount of autoantigen that is recognized by the immune system. When a patient is first diagnosed, the number of auto-antibodies detected is limited therefore the number of auto-antigens is also limited. However, as the autoimmune disease progresses the patient will develop more auto-antibodies against more auto-antigens. This is all caused by the sloppiness of T cell help to B cells. Ex: in Lupus, CD4 T cells that are specific for one epitope of a macromolecular complex can provide help to B cells specific for other accessible epitopes of the complex
Discuss the general usefulness of IVIg, RhoGAM, and other antibody preparations used in the therapeutic treatment of humans.
IVIg is intravenous immunoglobulin that is concentrated human IgG that is pooled from healthy human donors to treat primary antibody immune deficiencies, but now it can be used as an interfering anti-idiotypic antibody to block autoantibodies, inhibit naïve B cells, and overwhelm FcgR.
RhoGAM is used in the prevention of hemolytic disease of the newborn in which polyclonal antibody is purified from pooled Rh-negative mother who has Rh antibody Monoclonal antibody treatments are used to target and kill tumor cells or as immunosuppressants.
CHECK: Describe how monoclonal antibody preparations differ from polyclonal antibody preparations (aka, antiserum).
Monoclonal antibodies are antibody preparations in which antibody is all identical and is produced by a cell clone called a hybridoma
Identify specific monoclonal antibody therapies used to treat Rheumatoid Arthritis and other destructive autoimmune disorders.
Anti-TNF alpha is a blocking monoclonal antibody that is used to treat rheumatoid arthritis (it blocks joint destruction)
Anti-alpha 4 integrin blocks the homing of inflammatory cells which prevents autoimmune tissue destruction
Anti-IL-1 or anti-IL-6 antibodies interfere with macrophage inflammatory cytokines with anti-TNF alpha doesn’t work
Identify which types of hypersensitivity responses can cause autoimmune disorders, and which of these is most encountered.
Type II, III, and IV hypersensitivity responses cause autoimmune disorders, most commonly encountered is: Type II
CHECK: Be able to match the autoimmune endocrine disorders (Chronic Autoimmune Thyroiditis, Grave’s disease, Addison’s disease, and Type 1 diabetes mellitus) with the autoantibodies that may be observed in each disease, the serological testing done to diagnose the disease (if appropriate), and the immune mechanism that is responsible for the observed tissue destruction.
Chronic autoimmune thyroiditis: auto-antibodies observed: anti-thyroglobulin and anti-thyroid peroxidase (aka thyroid microsomal antigen), serological testing done to diagnose: enzyme immunoassay (most common), particle agglutination, or indirect immunofluorescence, immune mechanism responsible for tissue destruction: thyroid gland is infiltrated w/ lymphocytes, macrophages, and plasma cells, and germinal centers actually form in gland. Although auto-antibody is found, Tc destruction of thyroid epithelial cells is thought to ultimately cause the disease. Type IV hypersensitivity
Grave’s disease:
- Auto-antibodies observed: antibody to thyroid stimulating hormone receptor (anti-TSH-R)
- Serological testing done to diagnose: Most commonly done without serological testing- Assays for T3, T4, and TSH performed
- Immune mechanism responsible for tissue destruction: antibody acts as a receptor ligand (mimics TSH) and stimulates excessive T3 and T4 secretion
Addison’s disease:
- Auto antibodies observed: anti-21-hydroxylase antibody
- Serological testing done to diagnose: Not serological testing- chemistry tests for elevated serum ACTH and plasma renin
- Immune mechanism responsible for tissue destruction: autoantibodies destroy the adrenal cortex (type II hypersensitivity).
Type 1 diabetes mellitus:
- Auto-antibodies observed: anti-GAD (glutamic acid decarboxylase) antibody, anti-IA-2 (transmembrane tyrosine phosphate protein) antibody, and IAA (insulin antibody)
- Serological testing done to diagnose: Not serological testing- Fasting hyperglycemia and elevated hemoglobin A1C
- Immune mechanism responsible for tissue destruction: Autoimmune Tc destruction of pancreatic beta cells that normally secrete insulin (Type IV hypersensitivity)
Identify four autoimmune diseases that have a much higher incidence rate (> 5 times) in women than in men.
- Hashimoto’s thyroiditis
- Grave’s disease
- systemic lupus erythematosus
- Addison’s disease
Describe the general cause of Celiac Disease, auto-antibodies that can be used to diagnose it, and why dermatitis herpetiformis is associated with this disease.
During digestion, tissue transglutaminase (TTG) delaminates the gliadin component of gluten, and the modified gliadin stimulates a T cell response against new antigen. The autoantibodies that are used to diagnose: IgA anti-TTG antibodies, IgA anti-gliadin antibodies, and IgA anti-endomysium. Dermatitis herpetiformis is associated with this disease because of the high IgA anti-tissue transglutaminase
Identify the two forms of Inflammatory Bowel Disease in humans. Which of those can be associated with ANCA, and which ANCA pattern it is associated with (cANCA or pANCA)?
- ulcerative colitis - only inflames large intestine
- crohns disease- can inflame all of intestinal tract from mouth to anus
ANA( anti-neutrophil antibodies) are most common seen in patients with ulcerative colitis that have vasculitis. These patients usually have a pANCA (peripheral) pattern
Identify the autoantibodies associated with Pernicious Anemia and the vitamin deficiency they can cause.
Autoantibodies: anti-intrinsic factor antibody (most common) and anti-Parietal cell antibody.
Causes megaloblastic anemia due to cobalamin deficiency (vitamin B12)
Identify the autoantigen that is targeted in Myasthenia gravis, the disease pathophysiology, the immune mechanism(s) responsible for the disease, and the laboratory test used for diagnosis.
Auto-antigen that is targeted: ACH receptor
Disease pathophysiology: Antibody blocks binding to ACH-R and increased receptor uptake by muscle cell so that an action potential cannot occur
Immune mechanisms responsible for disease: Anti-ACH-R antibodies increase ACH-R recycling (remove it from cell surface) and blood ACR binding to ACH-R
Laboratory test used for diagnosis: Detection of anti-ACH-R antibody by precipitation radioimmunoassay
Identify the autoantigens that are targeted in Multiple sclerosis, the disease pathophysiology, and the immune mechanism(s) responsible for the disease.
Auto-antigen that is targeted: MBP (myelin basic protein) and MOG (myelin oligodendrocyte glycoprotein)
Disease pathophysiology: Inflammatory autoimmune disease of myelin located in the CNS).
Immune mechanisms responsible for disease: Auto-antigens are targeted by both antibody and T cells (Th1 and Tc) and they both play a role in myelin destruction
