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Chapter: Basic & Clinical Pharmacology : Immunopharmacology

Abnormal Immune Responses

Whereas the normally functioning immune response can success-fully neutralize toxins, inactivate viruses, destroy transformed cells, and eliminate pathogens.


Whereas the normally functioning immune response can success-fully neutralize toxins, inactivate viruses, destroy transformed cells, and eliminate pathogens, inappropriate responses can lead to extensive tissue damage (hypersensitivity) or reactivity against self antigens (autoimmunity); conversely, impaired reactivity to appro-priate targets (immunodeficiency) may occur and abrogate essen-tial defense mechanisms.


Hypersensitivity can be classified as antibody-mediated or cell-mediated. Three types of hypersensitivity are antibody-mediated (types I–III), while the fourth is cell-mediated (type IV). Hypersensitivity occurs in two phases: the sensitization phase and the effector phase. Sensitization occurs upon initial encounter with an antigen; the effector phase involves immunologic memory and results in tissue pathology upon a subsequent encounter with that antigen.

Type I—Immediate, or type I, hypersensitivity is IgE-mediated,with symptoms usually occurring within minutes following the patient’s reencounter with antigen. Type I hypersensitivity results from cross-linking of membrane-bound IgE on blood basophils or tissue mast cells by antigen. This cross-linking causes cells to degran-ulate, releasing substances such as histamine, leukotrienes, and eosinophil chemotactic factor, which induce anaphylaxis, asthma, hay fever, or urticaria (hives) in affected individuals (Figure 55–5). A severe type I hypersensitivity reaction such as systemic anaphylaxis (eg, from insect envenomation, ingestion of certain foods, or drug hypersensitivity) requires immediate medical intervention.

Type II—Type II hypersensitivity results from the formationof antigen-antibody complexes between foreign antigen and IgM or IgG immunoglobulins. One example of this type of hypersen-sitivity is a blood transfusion reaction that can occur if blood is not cross-matched properly. Preformed antibodies bind to red blood cell membrane antigens that activate the complement cas-cade, generating a membrane attack complex that lyses the trans-fused red blood cells. In hemolytic disease of the newborn, anti-Rh IgG antibodies produced by an Rh-negative mother cross the placenta, bind to red blood cells of an Rh-positive fetus, and damage them. The disease is prevented in subsequent pregnancies by the administration of anti-Rh antibodies to the mother 24–48 hours after delivery (see Immunosuppressive Antibodies, below).

Type II hypersensitivity can also be drug-induced and may occur during the administration of penicillin (for example) to allergic patients. In these patients, penicillin binds to red blood cells or other host tissue to form a neoantigen that evokes production of antibodies capable of inducing complement-mediated red cell lysis. In some circumstances, subsequent administration of the drug can lead to systemic anaphylaxis (type I hypersensitivity).

Type III—Type III hypersensitivity is due to the presence ofelevated levels of antigen-antibody complexes in the circulation that ultimately deposit on basement membranes in tissues and vessels. Immune complex deposition activates complement to produce components with anaphylatoxic and chemotactic activi-ties (C5a, C3a, C4a) that increase vascular permeability andrecruit neutrophils to the site of complex deposition. Complex deposition and the action of lytic enzymes released by neutrophils can cause skin rashes, glomerulonephritis, and arthritis in these individuals. If patients have type III hypersensitivity against a particular antigen, clinical symptoms usually occur 3–4 days after exposure to the antigen.

Type IV: Delayed-type hypersensitivity— Unlike type I,II, and III hypersensitivities, delayed-type hypersensitivity (DTH) is cell-mediated, and responses occur 2–3 days after exposure to the sensitizing antigen. DTH is caused by antigen-specific DTH TH1 cells and induces a local inflammatory response that causes tissue damage characterized by the influx of antigen-nonspecific inflammatory cells, especially macrophages. These cells are

recruited under the influence of TH1-produced cytokines (Figure 55–6), which chemoattract circulating monocytes and neutrophils, induce myelopoiesis, and activate macrophages. The activated macrophages are primarily responsible for the tissue damage associated with DTH. Although widely considered to be deleterious, DTH responses are very effective in eliminating infec-tions caused by intracellular pathogens such as Mycobacterium tuberculosis and Leishmania species. Clinical manifestations of DTH include tuberculin and contact hypersensitivities. Tuberculosis exposure is determined using a DTH skin test. Positive responses show erythema and induration caused by accu-mulation of macrophages and DTH T (TDTH) cells at the site of the tuberculin injection. Poison ivy is the most common cause of contact hypersensitivity, in which pentadecacatechol, the lipo-philic chemical in poison ivy, modifies cellular tissue and results in a DTH T-cell response.


Autoimmune disease arises when the body mounts an immune response against itself due to failure to distinguish self tissues and cells from foreign (nonself ) antigens or loss of tolerance to self. This phenomenon derives from the activation of self-reactive T and B lymphocytes that generate cell-mediated or humoral immune responses directed against self antigens. The pathologic conse-quences of this reactivity constitute several types of autoimmune diseases. Autoimmune diseases are highly complex due to MHC genetics, environmental conditions, infectious entities, and dys-functional immune regulation. Examples of such diseases include rheumatoid arthritis, systemic lupus erythematosus, multiple scle-rosis, and insulin-dependent diabetes mellitus (type 1 diabetes). In rheumatoid arthritis, IgM antibodies (rheumatoid factors) are pro-duced that react with the Fc portion of IgG and may form immune complexes that activate the complement cascade, causing chronic inflammation of the joints and kidneys. 

In systemic lupus erythe-matosus, antibodies are made against DNA, histones, red blood cells, platelets, and other cellular components. In multiple sclerosis and type 1 diabetes, cell-mediated autoimmune attack destroys myelin surrounding nerve cells and insulin-producing islet beta cells of the pancreas, respectively. In type 1 diabetes, activated CD4 TDTH cells that infiltrate the islets of Langerhans and recognize self islet beta cell peptides are thought to produce cytokines that stimu-late macrophages to produce lytic enzymes, which destroy islet beta cells. Autoantibodies directed against the islet beta cell antigens are produced, but do not contribute significantly to disease.

A number of mechanisms have been proposed to explain auto-immunity:

Exposure of antigens previously sequestered from the immune system (eg, lens protein, myelin basic protein) to self-reactive T lymphocytes.


Molecular mimicry by invading pathogens, in which immune responses are directed at antigenic determinants on pathogens that share identical or similar epitopes with normal host tissue. This phenomenon occurs in rheumatic fever following Streptococcus pyogenes infection, in which heart damage isthought to arise from an immune response directed against streptococcal antigens shared with heart muscle. The suggested viral etiology of autoimmune diseases has been ascribed to immune responses (both cell-mediated and humoral) directed against virus epitopes that mimic self antigens.


Inappropriate expression of class II MHC molecules on the membranes of cells that normally do not express class II MHC (eg, islet beta cells). Increased expression of MHC II may increase presentation of self peptides to T helper cells, which in turn induce CTL, TDTH, and B-lymphocyte cells that react against self antigens.

Immunodeficiency Diseases

Immunodeficiency diseases result from inadequate function in the immune system; the consequences include increased susceptibility to infections and prolonged duration and severity of disease. Immunodeficiency diseases are either congenital or arise from extrinsic factors such as bacterial or viral infections or drug treat-ment. Affected individuals frequently succumb to infections caused by opportunistic organisms of low pathogenicity for the immuno-competent host. Examples of congenitally acquired immunodefi-ciency diseases include X-linked agammaglobulinemia, DiGeorge’s syndrome, and severe combined immunodeficiency disease (SCID) due to adenosine deaminase (ADA) deficiency.

X-linked agammaglobulinemia is a disease affecting males that is characterized by a failure of immature B lymphocytes to mature into antibody-producing plasma cells. These individuals are susceptible to recurrent bacterial infections, although the cell-mediated responses directed against viruses and fungi are preserved. DiGeorge’s syndrome is due to failure of the thymus to develop, resulting in diminished T-cell responses (TDTH, CTL), while the humoral response remains functional, but does not benefit from T-cell help.

The ADA enzyme normally prevents the accumulation of toxic deoxy-ATP in cells. Deoxy-ATP is particularly toxic to lym-phocytes, and leads to death of T and B cells. Absence of the enzyme therefore results in SCID. Infusion of the purified enzyme ( pegademase, from bovine sources) and transfer of ADA gene-modified lymphocytes have both been used successfully to treat this disease.

AIDS represents the classic example of immunodeficiency dis-ease caused by extrinsic viral infection, in this instance the human immunodeficiency virus (HIV). This virus exhibits a strong tro-pism for CD4 T helper cells; these become depleted, giving rise to increased frequency of opportunistic infections and malignancies in infected individuals. AIDS is also characterized by an imbalance in TH1 and TH2 cells, and the ratios of cells and their functions are skewed toward TH2. This results in loss of cytotoxic T-lymphocyte activity, loss of delayed hypersensitivity, and hyper-gammaglobulinemia.

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