Hypersensitivity Flashcards
Which of the hypersensitivity reactions is cell mediated?
Type IV
What antibody mediates type I reactions?
IgE
What antibodies mediate types II and III reactions?
IgG and IgM
What are type I reactions also referred to as?
Allergic reaction, immediate hypersensitivity, or anaphylactic hypersensitivity
In type I reactions, allergens (ie, antigens) are presented to Th2 cell. The activated Th2 cells then release IL-4, IL-5 and IL-13. Describe the function of each of these cytokines in type I reactions:
IL-4: key factor that causes B cells to switch from IgM to IgE production, induces Th2 cell differentiation
IL-5: Activates eiosinophils
IL-13: promotes IgE production by B cells, induces Th2-cell differentiation of T cells, causes mucussecretion in epithelial cells, and enhances smooth muscle contraction
What are the steps of a type I reaction? Include processes that occur at the time of initial antigen exposure and the subsequent exposure.
IgE Ab is induced by an allergen–>IgE binds to Fc receptors on the surface of mast cells/basophils. When the individual is reexposed to the allergen the second time–>the allergen causes cross linking of bound IgE molecules–>the cross linking activates IgE mediated degranulation in mast cells/basophils with release of various mediators the most important of which is histamine, the mediator responsible for the anaphylactiv symptoms.
Type I reactions involve both primary and secondary mediators. Explain the difference between the two.
Primary mediators: preformed molecules stored in granules that are directly released
Secondary mediatiors: generated de novo as a consequence of mast cell/basophil activation
Histamine and proteases/hydrolases are primary mediators. What are their functions?
Histamine: vasodilation, increases vascular permeability and plasma leak (edema formation), smooth muscle contraction increases secretions (nasal, respiratory)
Protease/hydrolases: tissue damage, activate complement, cleavage of membrane receptors
Leukotrienes B4, C4, D4, and E4 and cytokines are secondary mediators. What are their functions?
Leukotrienes: B4–>recruits white blood cell (WBC). C4/D4/E4–>vasodilation, increases vascular permeability
Cytokines: mediate the inflammatory response of the late phase
What are the two phases of type I hypersensitivity reactions?
- Immediate phase: rapid degranulation of preformed mediators in mast cells/basophils within minutes of reexposure to antigen that cross-links the cell-bound IgE
- Late phase: 2-48 hours after antigen exposure; secondary mediators cause an influx, maturation, and activaton of inflammatory cells and increase teir survival in tissue
What are the symptoms of the immediate phase of type I reactions?
Edema, erythema, wheal and flare reaction in the skin, itching (skin, eye, nose), runny nose, wheezing
What are the common clinical manifestations of type I hypersensitivity reactions?
Skin: urticaria (hives), eczema
Airways: rhinitis, asthma
Eyes: conjunctivitis
What are the consequences of IgE mediated responses in the GI tract, airways and blood vessels?
GI tract: increased fluid secretion, increased peristalsis–>expulsion of GI tract contents (diarrhea, vomiting)
Airways: decreased diameter, increased mucus secretion–>expulsion of contents (phlegm, coughing)
BLOOD VESSELS: increased blood flow, increased permeability–>edema, inflammation, and increased lymph flow takes Ag to lymph nodes
What is the most severe form of type I hypersensitivity reactions?
Systemic anaphylaxis, which manifests as life-threatening bronchoconstriction and system vasodilation (eg, hypotensive shock)
What are some common causes of anaphylaxis?
Peanut, bee venom, drug, and latex allergy
What drugs are commonly given to prevent anaphylactic reactions?
Antihistamines, corticosteroids, and cromolyn sodium. Epinephrine can be given as treatment for anaphylactic reactions
How does cromolyn sodium work on mast cells?
It stabilizes mast cell membranes preventing degranulation
What do patients with atopic disorders (asthma, eczema and urticaria) have elevated levels of?
IgE, Th2 cytokines
Drugs commonly cause hypersensitivity reactions by acting as haptens. What is a hapten and how does this induce hypersensitivity reactions?
A hapten is a molecule, which by itself, cannot induce an immune response. The hapten, usually a drug or its metabolite binds to an endogenous protein that then induces antibody formation. The antibody reacts to the hapten (drug or its metabolite) upon subsequent exposure
What are type II hypersensitivity reactions also known as?
Cytotoxic hypersensitivity
What reaction occurs in type II hypersensitivity?
Antibodies against endogenous cell membrane antigens fix complement causing complement mediated lysis via membrane attack complex
For each disease associated with type II hypersensitivity, name the target: Warm/cold autoimmune hemolytic anemia: Erythroblastosis fetalis: Pernicious anemia Antineutrophil cytoplasmic antibodies (ANCA) vasculitis C-ANCA P-ANCA Goodpasture syndrome
Warm/cold autoimmune hemolytic anemia: Self RBC membrane proteins (warm=IgG; cold=IgM)
Erythroblastosis fetalis: Fetal D-Rh antigen
Pernicious anemia: Intrinsic factor (binds B12)
(ANCA) vasculitis: Neutrophil granule protein
C-ANCA: PR3
P-ANCA: Myeloperoxidase
Goodpasture syndrome: Alveolar and glomerular basement membrane
Rheumatic fever: Graves Disease: Myasthenia Gravis: Lambert-Eaton myasthenic syndrome: Pemphigus vulgaris: Bullous pepmigoid:
Rheumatic fever: Myocardial ags that cross react with streptococcal ags (possibly the streptococcus M protein)
Graves Disease: Thyroid stimulating hormone (TSH) receptor
Myasthenia Gravis: Acetylcholine receptor
Lambert-Eaton myasthenic syndrome: Presynaptic Ca2+ channels
Pemphigus vulgaris: Epidermal desmosomes
Bullous pepmigoid: Epidermal-dermal hemi-desmosomes
What drugs are associated with warm autoimmune hemolytic anemia? Of these, which drugs are associated with haptens? Which drugs generate autoantibodies?
Penicillin and quindine are hapten forming. alpha methyl dopa generates auto antibodies
What test is positive in warm autoantibody disease?
Direct antiglobulin (Coombs test)
Cold autoimmune hemolytic disease has an acute and chronic form. What infections are associated with the acute form? What type of neoplasm is associated with the chronic form?
Acute form is associated with mycoplasma pneumoniae and infectious mononucleosis (eg, Epstein-Barr virus [EBV]). Chronic form is associated with lymphoid neoplasms
How is the autoantibody in Grave disease different from other autoantibodies?
The autoantibody in Grave disease, a thyroid stimulating immunoglobulin (TSI) actually binds and activates the TSH receptor
What type II disease is mediated by an autoantibody that shares the same target as exfoliatin (Staphylococcus toxin in scaled skin syndrome)?
Pemphigus vulgaris
What region of autoantibodies attaches to the ag in type II reactions? What region binds the complement?
IgG or IgM attaches to the ag at their Fab region and attaches complement at their Fc region
Which of the hypersensitivity reactions are antibody mediated?
Types I, II and III
What are type III hypersensitivity reactions also known as?
Immune complex hypersensitivity
In type III reactions formation of large antigen-antibody immune complexes deposit into tissues and fix complement. How does activation of complement result in tissue damage? How does this differ from type II hypersensitivity?
Complement activation recruits neutrophils, which release proteolytic enzymes and cause tissue damage. This differs from type II in which tissue damage is caused by autoantibody-mediated complement activation (not by formation of large immune complexes).
One important factor that determines if antigen-antibody complexes deposit into tissue is the relative amount of antigen versus antibody. Why do antigen-predominant complexes typically form pathogenic deposits?
Antigen-ab complexes are cleared when mononuclear phagocytes bind to ab, resulting in endocytosis of the complex. In ag-predominant complexes, fewer abs means less clearance and a propensity to form pathogenic deposits.
What is a pathology term used to describe type III inflammation in vessels?
Fibrinoid necrosis (eosinophilic staining accumulation)
What are the two typical type III hypersensitivity reactions?
- Arthus reaction: local deposition of immune complexes
2. Serum sickness: systemic inflammatory response to immune complexes deposits throughout the body
Describe how an Arthus reaction is evoked?
Antigen is subcutaneously injected into a host with preformed antibodies to this antigen causing local edema and possible ulceration
Hypersensitivity pneumonitis (farmer lung) is an Arthus reaction caused by inhalation of what bacteria?
Thermophilic actinomycetes
What is the typical clincal presentation of serum sickness?
Fever, hives, arthralgia, lymphadenopathy, splenomegaly, and eosinophilia appear days to weeks after ag exposure
Mnemonic: Serum sickness HEALS For Weeks: Hives, Eosinophilia, Arhralgia, Lymphadenopathy, splenomegaly, fever
What drug is associated with serum sickness?
Penicillin–it can cause type I, II and III via hapten formation
What are well known diseases that are resulted from type III immune complex deposition?
Poststreptococcal glomerulonephritis, rheumatoid arthritis, and systemic lupus erythematosus
What are type IV hypersensitivity reactions also known as?
Delayed type hypersensitivity (DTH)
What are the two types of type IV hypersensitivity?
- Classic (tuberculin-like) DTH
2. Contact dermatitis
In the first step of classic DTH, macrophages present antigens to CD4+ helper cells and induce CD4+ cells to become what specific subtype? What cytokine secreted by macrophages drives this process?
Macrophages induce CD4+ T cells to mature into Th1 cells. IL-12 is the cytokine that drives this process
These Th1 cells often remain in the circulatory system as memory cells. When the body is exposed to the ag for a subsequent time, what cells do these Th1 cells activate? What cytokine secreted by the Th1 cells drives this process?
Th1 cells activate macrophages. IFN-y is the cytokine that drives this process
What functions are enhanced when a macrophage is activated?
Increased phagocytosis, increased antimicrobial potency, increased antigen presentation, and further induction of inflammation
What functions are enhanced when a macrophage is activated?
Increased phagocytosis, increased antimicrobial potency, increased ag presentation, and further induction of inflammation
What is seen histopathologically in classic DTH?
Granuloma: central core of epithelioid cells (type of y-IFN activated macrophages) with a rim of lymphocytes
Which pathogens trigger classic DTH?
Mycobacteria and fungi
A positive tuberculin skin test is a classic DTH. Describe how a positive test presents
Minimal change in the first few hours followed by erythema and in duration of 48 to 72 hours
How does contact dermatitis differ from classic DTH?
In contact dermatitis, previously sensitized Th1 cells enter the dermis and cause cytokine-mediated cell necrosis as opposed to the granulomatous reactions seen in classic DTH
What are common contact allergens?
Plants (poison ivy/oak), chemicals, soaps, jewelry metal, topical drugs
What are common symptoms of contact dermatitis?
Erythema, pruritus, and necrosis of skin with formation of large blisters within 24 hours
What is the role of MHC class II proteins on donor cells in graft rejection?
Recognized by helper T cells of the host–>proliferation, cytokine production, and “help” to activate cytotoxic T cells to kill the donor cells
What are the immunological contraindications to organ transplantation?
ABO blood group incompatibility, presence of preformed human leukocyte antigen (HLA) antibodies in the recipient’s serum
What does a lymphocyte cross match do?
Screens for recipient anti-HLA antibodies against donor lymphocytes
What are the typical mechanisms by which transplant recipients are presensitized to donor antigens?
Pregnancy, previous transplantation, blood transfusion
The mixed lymphocyte reaction is used for MHC class II antigen (D loci) matching. How does it work?
Recipient lymphocytes are mixed with irradiated donor lymphocytes and assessed from proliferation. The degree of compatibility is inversely proportional to proliferation by the recipient cells
What are the four classes of grafts?
- Allograft (same species)
- Isograft or syngeneic graft (MZ twins)
- Autograft (same individual)
- Xenograft (transplant bw species)
What are the three rejection reactions?
- Hyperacute rejection
- Acute rejection
- Chronic rejection
What is the time frame of hyperacute rejection?
Minutes to hours
What mediates hyperacute rejection and what is the specific target on the graft?
Preformed abs against graft vascular endothelial ags.
What is the cellular results of hyperacute rejection?
complement activation leading to endothelial damage, neutrophilic inflammation, and thrombosis
How can hyperacute rejection be avoided?
Matching and cross matching the ABO blood group of donor and recipient
What is the time frame of acute rejection? what if the recipient is treated with immunosuppressive therapy?
Within days of transplantation in a nonimmunosuppresed recipient. If immunosuppressed, rejection may occur after months to years
What mediates acute rejection and what are the targets of this response?
- T-cell mediated response (CD4+ and CD8+) to donor vasculature and parenchyma
- Humoral rejection with antibodies against vasculature
How does each T cell participate in acute rejection?
CD8+ cytotoxic T lymphocyte (CTL) recognizes and directly kills donor cells. CD4+ Th1 cells mediate a DTH (type IV) response
What causes the delay in acute rejection versus hyperactive rejection?
Time lag is due to T cell activation/differentiation and antibody production
Accelerated acute rejection occurs when a second allograft from the same donor is given to a sensitized recipient. What is the prinicipal mediator of this process?
The presence of memory (presensitized T cells)
How long does accelerated acute rejection take?
5-6 days in the absence of immunosuppresion
What is the time frame for chronic rejection?
Months to years
What is the main pathologic finding of chronic rejection?
Artherosclerosis of vascular endothelium and proliferation of intimal smooth muscle cells
What cell causes the vascular pathology that develops in chronic rejection?
It is unclear, but is a mixture of immune and nonimmune mediated processes
What is the hypothesized cause of chronic rejection?
Damage of the allograft during transplant, drug toxicity, and incompatibility of minor histocompatibility antigens
What causes minor histocompatibility mismatches between the donor and recipient?
Polymorphic self antigens: self proteins that differ in amino acid sequence between individuals
What are the drugs used for postoperative immunosuppresion?
Calcineurin inhibitors: cyclosporine and tacrolimus
Cell cycle inhibitors: azathioprine and mycophenolate mofetil
Glucocorticoids: prednisone
Antilymphocyte antibbodies: OKT3, Thymoglobulin mTOR inhibitors: rapamycin
What is the mechanism behind the use of OKT3?
Antibody directed against CD3 which is found on all T cells, leading to decreased T cell numbers
How are cyclosporine and tacrolimus immunosuppressive?
Cyclosporine prevents the activation of T cells by inhibiting the calcineurin phosphatase which blocks the synthesis of IL-2 and IL-2 receptor
How is azathioprine immunosuppressive?
Azathioprine is an inhibitor of purine synthesis, thus blocking DNA replication and the proliferation of T cells
What are some of the problems associated with immunosuppressive therapy?
Drug toxicities, kidney damage, increased viral infections (e.g, cytomegalovirus (CMV), herpes simplex virus (HSV), increased viral associated malignancies (eg, EBV), and other opportunisitic infections
What complication is of particular concern in bone marrow transplants?
Graft vs. host disease (GVHD) reaction: T cells in the transplanted marrow react against alloantigens of the immunocompromised host
What are the three requirements for GVHD to occur?
- The graft must contain immunocompetent T cells
- The host must be immunocompromised so that the graft T cells are not destroyed
- The recipient must express antigens foreign to the donor
How can GVHD occur even when the donor and recipient have identical classes I and II MHC proteins?
Differences in minor histocompatibility antigens
What treatments reduce the likelihood of GVHD?
Treating the donor tissue with antithymocyte globulin or monoclonal antibodies before grafting and using cyclosporine
