Hypersensitivity Reactions

Question 1

Innate (natural) Immunity

Answer 1

refers to pre-existing, nonspecific defense mechanisms present prior to infection that have evolved to recognize microbial pathogens and protect the individual against infection. These defense mechanisms can also recognize nonmicrobial antigens that have been released during cell death or injury. Major components include:

Epithelial barriers
Phagocytic cells (neutrophils and monocytes/macrophages)
Eosinophils, basophils, mast cells
Dendritic cells
Natural killer cells (NK cells)
Plasma proteins (complement system, mannose-binding lectin, C-reactive protein, lung surfactant)

Question 2

Adaptive (acquired, specific) immunity

Answer 2

refers to reactive mechanisms that are stimulated by the specific microbe and are capable of recognizing microbial and nonmicrobial substances (antigens). The term “immune response” refers to adaptive immunity.

The adaptive immune system consists of lymphocytes and their products, including antibodies.

There are two types of adaptive immunity:

Humoral immunity: protects against extracellular microbes and toxins.
Cell-mediated immunity: protects against intracellular microbes, tumor cells.

Question 3

Humoral immunity

Answer 3

protects against extracellular microbes and toxins.

Question 4

Cell-mediated immunity

Answer 4

protects against intracellular microbes, tumor cells.

Question 5

Naïve lymphocytes

Answer 5

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

Question 6

Activated lymphocytes

Answer 6

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

Question 7

CD4 T cells

Answer 7

helper
secrete cytokines (IL-2 causes proliferation of CD4/CD8 T cells
IFN-Gamma causes activation of macrophages
help B cells become antibody producing plasma cells

Question 8

CD8 T cells

Answer 8

cytotoxic/ suppressor
kill virus-infected, neoplastic, and donor graft cells

Question 9

B cells

Answer 9

differentiate into plasma cells that produce imunoglobulins to kill encapsulated bacteria
act as APCs that interact with CD4 cells

Question 10

NK Cells

Answer 10

Kill virus-infected and neoplactic cells
release IFN-Gamma

Question 11

macrophages

Answer 11

involved in phagocytosis and cytokine production
Act as APCs to T cells

Question 12

Dendritic cells

Answer 12

act as APCs to T cells

Question 13

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

Answer 13

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 14

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

Answer 14

T-cell receptors: 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).

B lymphocytes: 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 15

Generative lymphoid organs (primary or central)

Answer 15

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

Question 16

Peripheral lymphoid organs (secondary)

Answer 16

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 17

Major Histocompatibility Complex (MHC)

Answer 17

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)

Question 18

Class I MHC molecules

Answer 18

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

Question 19

Class II MHC molecules

Answer 19

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 20

Describe two uses of HLA testing

Answer 20

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).

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 21

Cell-mediated immunity

Answer 21

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 22

Humoral immunity

Answer 22

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

Question 23

HYPERSENSITIVITY REACTIONS

Answer 23

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 24

IMMEDIATE (TYPE I) HYPERSENSITIVITY

Answer 24

Defined as 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.

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).

Question 25

Atopy

Answer 25

Susceptibility to immediate hypersensitivity reactions is genetically determined. Atopy refers to the predisposition to develop localized immediate hypersensitivity reactions. A positive family history of allergy is found in 50% of atopic individuals. Atopic individuals also tend to have higher serum IgE levels and more IL-4-producing TH2 cells.

Question 26

Describe the mechanisms involved in the immediate reactions of type I hypersensitivity reactions

Answer 26

Sequence of events in immediate (type I) hypersensitivity. Immediate hypersensitivity reactions are initiated by the introduction of an allergen, which stimulates TH2 responses and IgE production in genetically susceptible individuals. IgE binds to Fc receptors (FcεRI) on mast cells, and subsequent exposure to the allergen activates the mast cells to secrete the mediators that are responsible for the pathologic manifestations of immediate hypersensitivity. In some individuals, immediate hypersensitivity reactions are triggered by temperature extremes and exercise (non-atopic allergy) and do not involve T helper cells or IgE. In these cases it is believed that the mast cells are abnormally sensitive to activation by various non-immune stimuli.

Question 27

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

Answer 27

Immediate hypersensitivity. A, Kinetics of the immediate and late-phase reactions. The immediate vascular and smooth muscle reaction to allergen develops within minutes after challenge (allergen exposure in a previously sensitized individual), and the late-phase reaction develops 2 to 24 hours later. B, C, Morphology: The immediate reaction (B) is characterized by vasodilation, congestion, and edema, and the late-phase reaction (C) is characterized by an inflammatory infiltrate rich in eosinophils, neutrophils, and T cells

Question 28

Define localized allergic reaction, and list some common examples.

Answer 28

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 29

Describe the treatment and prevention of localized allergic reactions.

Answer 29

In some cases, it becomes desirable to identify the offending allergen. This can be done with skin prick test (histamine-mediated wheal and flare reaction) or with allergy blood tests (allergy screening test to measure IgE antibodies to specific allergens).

Treatment typically involves:

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 (more on this next slide).

Question 30

Define systemic anaphylaxis, and describe the mechanisms and clinical findings in systemic anaphylaxis. List some of the common inciting agents in fatal systemic anaphylaxis.

Answer 30

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

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.

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.

In some patients with honeybee allergy, venom immunotherapy is used to prevent future attacks. This form of desensitization therapy involves repeated injections of the allergen in increasingly greater amounts resulting in the production of IgG antibodies that can attach to allergens and prevent them from binding to mast cells.

Question 31

Define type II hypersensitivity reaction

Answer 31

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.

Question 32

Mechanisms of antibody-mediated (type 2) injury

Answer 32

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 33

goodpasture syndrome

Answer 33

noncollagenous protein in basement membranes of kidney glomeruli and lung alveoli targeted
complement and Fc receptor mediated inflammation

Question 34

Pemphigus vulgaris

Answer 34

Pemphigus vulgaris is due to autoantibodies directed against desmogleins 1 and 3 which are found in desmosomes.

Question 35

IMMUNE COMPLEX-MEDIATED (TYPE III) HYPERSENSITIVITY

Answer 35

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.

Complement is consumed as part of the pathogenic process, and the levels of C3 can be used to monitor disease activity (low levels indicate active disease

Question 36

Examples of type 3

Answer 36

lupus, arthritis, serum sickness, polyarteritis nodosa, poststrep glomerulonephritis

Question 37

T CELL-MEDIATED (TYPE IV) HYPERSENSITIVITY

Answer 37

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:

Delayed-type hypersensitivity reaction

T cell mediated cytotoxicity

Question 38

Mechanisms of T cell–mediated (type IV) hypersensitivity reactions

Answer 38

A, In delayed-type hypersensitivity reactions, upon repeat exposure to the antigen, CD4+ TH1 cells (and sometimes CD8+ T cells, not shown) respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury. CD4+ TH17 cells contribute to inflammation by recruiting neutrophils (and, to a lesser extent, monocytes). Examples of this mechanism include the tuberculin reaction (PPD test), forms of granulomatous inflammation, and contact dermatitis. B, In some diseases, CD8+ cytotoxic T lymphocytes (CTLs) directly kill tissue cells. Examples of this mechanism include type I diabetes and graft rejection. APC, antigen-presenting cell.

Question 39

Mechanisms of granuloma formation

Answer 39

antigen presenting cell binds antigen, releases IL-12
CD4 Th1 cell activated, releases IL-2, TNF, and IFN-gamma
TNF promotes exvascularization of monocytes
IFN-gamma attracts monocytes
granuloma forms

Question 40

examples of type 4 reactions

Answer 40

diabetes
MS
arthritis (rheumatoid)
crohns
guillain-barre
dermatitis