Hypersensitivity Reactions Dr. Nelson 5/5/14

Question 1

Naive Lymphocytes

Answer 1

Mature lymphocytes which have not yet encountered the antigen for which they are specific for.

Question 2

Activated Lymphocytes

Answer 2

Differentiate into effector cells, which eliminate the offending organism, and memory cells, which can be reactivated upon second exposure.

Question 3

Effector Lymphocytes

Answer 3

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Question 4

Memory Lymphocytes

Answer 4

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Question 5

Describe the fxn of T-lymphocytes (both CD4+ and CD8+)

Answer 5

CD4+–>secrete cytokines (IL-2–>proliferation of CD4/CD8 T cells, IFN-gamma–>activation of macrophages); help B cells become antibody producing plasma cells.

CD8+–>kill virus-infected, neoplastic, and donor graft cells.

Question 6

Describe the fxn of B-lymphocytes

Answer 6

Differentiate into plasma cells that produce immunoglobulins to kill encapsulated bacteria (e.g. Streptococcus pneumonia). Act as APCs that interact w/ CD4 cells.

Question 7

Describe the fxn of NK cells

Answer 7

Kill virus-infected and neoplastic cells. Release IFN-gamma.

Question 8

Describe the fxn of macrophages

Answer 8

Involved in the phagocytosis and cytokine production. Act as APCs to T cells.

Question 9

Describe the fxn of dendritic cells

Answer 9

Act as APCs to T cells.

Question 10

Describe how light chain expression can be used to determine if a B-lymphocyte proliferation is clonal.

Answer 10

Clonal proliferations typically produce or express only one type of immunoglobulin, and thus the light chain will be of either the kappa or lambda type. Sometimes it can be difficult to distinguish a B cell reactive proliferation from a clonal (neoplastic) proliferation; use of Ig (immunoglobulin) gene rearrangement analysis can help.

Question 11

Describe the use of T-cell receptor gene rearrangement studies and B-cell immunoglobulin gene arrangement studies

Answer 11

Each T cell lymphocyte recognizes a specific cell bound antigen by means of an antigen specific T cell receptor (TCR); clonal (neoplastic) proliferations of T cells can sometimes be difficult to recognize, and use of TCR gene rearrangement analysis can be used to determine if a T-cell proliferation is clonal (neoplastic).

Question 12

Define generative lymphoid organ

Answer 12

Sites where T and B lymphocytes mature and become competent to respond to antigens (bone marrow and thymus).

Question 13

Define peripheral lymphoid organs

Answer 13

Sites where the adaptive immune response is initiated (lymph nodes, spleen, mucosal and cutaneous lymphoid tissues (GI tract, respiratory tract, skin); T and B lymphocytes are segregated into different regions in the peripheral lymphoid organs (e.g. in the lymph nodes, B cells are found in the follicles, T cells in the paracortical region; when B cells respond to an antigen get reactive germinal centers in the follicles); spleen responds to blood borne antigens, lymph node responds to antigens in the lymphatic fluid that drains to the lymph node.

Lymphocytes constantly recirculate between tissues and home to particular sites; naïve lymphocytes traverse the peripheral lymphoid organs where immune responses are initiated, and effector lymphocytes migrate to sites of infection and inflammation.

Question 14

Define MHC

Answer 14

The physiologic function of MHC molecules is to display peptide fragments of proteins for recognition by antigen specific T cells. In humans the MHC complex genes are found on chromosome 6 and are also known as the human leukocyte antigen (HLA) complex as they were initially detected on leukocytes. The MHC gene products are membrane bound glycoproteins which are found on all nucleated cells except mature red blood cells. The HLA system is highly polymorphic (many different alleles of each MHC gene). Key MHC gene products include:

Class I MHC molecules: coded by HLA-A, HLA-B, and HLA-C genes; display proteins that are derived from the cytoplasm (e.g. viral antigens), and are recognized by CD8+ T-lymphocytes and NK cells

Class II MHC molecules: coded by HLA-DP, HLA-DQ, and HLA-DR genes; display antigens that have been internalized into vesicles (such as extracellular microbes and soluble proteins) and are recognized by CD4+ T lymphocytes.

Question 15

Describe the two uses of HLA testing

Answer 15

1. A variety of diseases are associated with the inheritance of certain HLA alleles, and HLA testing can be used to determine disease risk (e.g. 90% of patients with ankylosing spondylitis are positive for HLA-B27).
2. HLA testing is also used in the transplantation workup, as close matches of HLA-A, HLA-B, HLA-C, and HLA-D in both the donor and graft recipient increase the chance of graft survival.

Question 16

Describe the key steps and fxns of cell-mediated immunity

Answer 16

Dendritic cells (DCs) capture microbial antigens from epithelia and tissues and transport the antigens to lymph nodes. During this process, the DCs mature, and express high levels of MHC molecules and costimulators. Naive T cells recognize MHC-associated peptide antigens displayed on DCs. The T cells are activated to proliferate and to differentiate into effector and memory cells, which migrate to sites of infection and serve various functions in cell-mediated immunity. CD4+ effector T cells of the TH1 subset recognize the antigens of microbes ingested by phagocytes, and activate the phagocytes to kill the microbes. CD4+ T cells also induce inflammation. CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells harboring microbes in the cytoplasm. Not shown are TH2 cells, which are especially important in defense against helminthic infections. Some activated T cells differentiate into long-lived memory cells. APC, antigen-presenting cell.

Question 17

Describe the key steps and fxn of humoral immunity

Answer 17

Naive B lymphocytes recognize antigens, and under the influence of TH cells and other stimuli (not shown), the B cells are activated to proliferate and to differentiate into antibody-secreting plasma cells. Some of the activated B cells undergo heavy-chain class switching and affinity maturation, and some become long-lived memory cells. Antibodies of different heavy-chain classes (isotypes) perform different effector functions, shown on the right.

Question 18

Define hypersensitivity reaction

Answer 18

Individuals previously exposed to an antigen are said to be sensitized; upon repeat exposure(s), some individuals will develop a pathologic immune reaction to the antigen. These pathologic immune reactions are called hypersensitivity disorders, reactions, or diseases. Some key general points are listed below:

Both exogenous and endogenous antigens may elicit hypersensitivity reactions (e.g., allergic reactions, autoimmune diseases).

The development of hypersensitivity diseases (both allergic and autoimmune disorders) is often associated with the inheritance of particular susceptibility genes (HLA and non-HLA genes).

Hypersensitivity reflects an imbalance between the effector mechanisms of immune responses and the control mechanisms that serve to limit such responses.

Hypersensitivity diseases can be classified on the basis of the immunologic mechanism that mediates the disease (however, multiple mechanisms may be occurring in some diseases).

Question 19

Define type I hypersensitivity

Answer 19

A rapid immunologic reaction occurring within minutes after an antigen combines with antibody bound to mast cells in individuals previously sensitized to the antigen (allergic reaction). The reaction is typically mediated by IgE antibody-dependant activation of mast cells.

Question 20

Define atopy

Answer 20

Predisposition to develop localized immediate hypersensitivity reactions.

Question 21

Describe the mechanisms involved in the immediate and late phase reactions of type I hypersensitivity reactions

Answer 21

Initial exposure to the antigen (allergen) results in activation of B cells with the production of IgE, which attaches to mast cells (this first step is called sensitization). Repeat exposure to the antigen (allergen) results in mast cell degranulation, with the release of chemical mediators, causing vasodilation, vascular leakage, smooth muscle spasm, and recruitment of leukocytes, particularly eosinophils. Eosinophils secrete major basic protein and eosinophil cationic protein, which are toxic to epithelial cells. Activated eosinophils and neutrophils also activate mast cells to release mediators, amplifying and sustaining the inflammatory response without additional exposure to the triggering antigen (late phase reaction).

Immediate reaction (minutes after repeat exposure to allergen)–> vasodilation, vascular leakage, and smooth muscle spasm.

Late phase reaction (2-24 hours after repeat exposure to allergen)–>leukocyte infiltration, epithelial damage, and bronchospasm.

Question 22

Define localized allergic reaction and list some common examples

Answer 22

• Allergic rhinitis (hay fever)
• Some forms of bronchial asthma (atopic forms)
• Urticaria (hives); can also reflect a systemic reaction, e.g. allergic drug reaction)
• Allergic gastroenteritis (food allergy)

Triggering allergens are numerous and include such things as pollens, molds, house dust, animal dander, foods, medications, blood products, venom from insect bites, etc.

Question 23

Describe the treatment and prevention of localized allergic reactions

Answer 23

• Avoiding the offending allergen, if possible.
• Use of various medications, such as antihistamines, corticosteriods, agents that inhibit release of histamine from mast cells, leukotriene modifiers (to name just a few).
• In some cases, immunotherapy (desensitization therapy) is also used .

Question 24

Define systemic anaphylaxis and describe the mechanism and clinical findings in systemic anyphylaxis

Answer 24

Refers to a life threatening systemic allergic reaction typically characterized by vascular shock, widespread edema, and difficulty breathing (massive mast cell activation).

Death can ensue within minutes if untreated (death is usually due to asphyxiation from upper airway edema or respiratory failure due to bronchial constriction/obstruction, and/or shock with cardiovascular collapse). Emergent treatment includes intramuscular epinephrine.

Question 25

Name some common inciting agents in fatal systemic anaphylaxis

Answer 25

Inciting agents include therapeutic agents (e.g. beta-lactam antiobiotics such as penicillin and cephalosporins, radiocontrast agents), exposure to food products (e.g. peanuts, seafood), insect toxin (e.g. bee or wasp sting), and latex allergy.

Question 26

Define type II hypersensitivity and list the mechanism of injury

Answer 26

Caused by antibodies that react with normal or altered cell surface antigens, or with antigens in the extracellular matrix. The involved antigens may be intrinsic to the cell membrane or matrix, or may take the form of an exogenous antigen (e.g. drug metabolite) that is adsorbed on a cell surface or matrix.

Mechanisms of antibody-mediated injury. A. Opsonization of cells by antibodies and complement components and ingestion by phagocytes. B, Inflammation induced by antibody binding to Fc receptors of leukocytes and by complement breakdown products. C, Anti-receptor antibodies disturb the normal function of receptors. In these examples, antibodies to the acetylcholine (ACh) receptor impair neuromuscular transmission in myasthenia gravis, and antibodies against the thyroid-stimulating hormone (TSH) receptor activate thyroid cells in Graves disease.

Question 27

Describe some examples of type II hypersensitivity as wells as Goodpasture’s syndrome

Answer 27

Disease– Target antigen– clinic manifestations

1. Autoimmune hemolytic anemia– red cell membrane proteins (Rh blood group antigens, I antigen)– hemolysis, anemia
2. autoimmune thrombocytopeniz purpura– platelet membrane proteins– bleeding
3. Pemphigus vulgaris–proteins in intercellular junctions of epidermal cells (epidermal cadherin)– skin vesicles (bullae)
4. Good pasture syndrome– non collagenous protein in basement membrane of kidney glomeruli and lung alveoli– nephritis, lung hemorrhage
5. Myasthenia gravis– acetycholine receptor– muscle weakness and paralysis
6. Insulin-resistant diabetes– insulin receptor– hyperglycemia, ketoacidosis
7. Pernicious anemia– intrinsic factor of gastric parietal cells– abnormal erythropoiesis– abnormal erythropoiesis, anemia

Question 28

Define type III hypersensitivity reaction and list the mechanism of injury

Answer 28

Caused by antigen-antibody complexes which elicit inflammation at the sites of deposition. The pathologic reaction begins when antigen combines with antibody in the circulation, and the circulating immune complexes are deposited in vessel walls. In some instances, the complexes can form at extravascular sites where the antigen has been “planted” previously (in situ immune complex deposition). The involved antigens can be exogenous or endogenous, and the sites of involvement can be systemic or localized. Blood vessels, as well as organs where blood is filtered to form other fluids, such as kidneys and synovium, are common sites of injury (vasculitis, glomerulonephritis, arthritis).

Key steps involve immune complex formation, immune complex deposition, and immune complex-mediated inflammation and tissue injury.

Question 29

Describe some examples of type III hypersensitivity and explain why the clinical manifestations can be quite diverse

Answer 29

SLE, poststreptococcal glomerulonerphritis, polyarteritis nodosa, reactive arthritis, serum sickness

Question 30

Define type IV hypersensitivity reaction and list the mechanism of injury

Answer 30

Caused by T cell mediated immunity (no antibodies involved).

CD4+ or CD8+ T lymphocytes are sensitized to exogenous or endogenous antigens. The resultant T cell immune response results in cell or tissue injury.

There are two mechanisms of T cell mediated (type IV) hypersensitivity:

1. Delayed-type hypersensitivity reaction
2. T cell mediated cytotoxicity

Question 31

Describe the mechanism of granuloma formation

Answer 31

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Question 32

List some common examples of type IV hypersensitivity

Answer 32

Type I diabetes, MS, Rheumatoid arthritis, Crohn disease, GBS, contact sensitivity