Basic Immunology
and Disorders of The Immune System

Francisco G. La Rosa, MD
Pathologist (AP/CP)

V. Immunosuppression and immunodeficiencies

A. Immunosuppression:

1. Physical
2. Chemical and biological
3. Action of Immunosuppressive agents

B. Primary Immunodeficiencies

1. Bruton’s disease
2. Isolated deficiency of IgA
3. Common variable immunodeficiency
4. Phagocytic cell defects:
    - Chronic granulomatous disease
    - Myeloperoxidase deficiency
    - Chediak-Higashi syndrome
    - Job’ syndrome
    - Lacy leukocyte syndrome
5. DiGeorge’s syndrome
6. Chronic mucocutaneous candidasis
7. Severe combined immunodeficiency (SCID)
8. Nezelof’s syndrome
9. Wiskott-Aldrich syndrome
10. Ataxia telangiectasia
11. Genetic deficiencies of the complement system

C. Secondary immunodeficiencies

1. Measles, leprosy, tuberculosis
2. AIDS

 
A. Immunosuppression

Physical immunosuppression:

1. Surgical manipulation can have a major impact on immune responsiveness.

a. Surgical removal of the bursa, or the thymus, or both in the neonatal period will block the development of immunologic competence in the correspondingly dependent lymphoid system. It is necessary that these future antibody-producing cells receive some influence from the bursa before they can become responsive in peripheral lymphoid tissues. Similarly, it is necessary for small lymphocytes to differentiate in the thymus before they can function in peripheral tissue.

b. Surgical removal of these tissues after immunologic development, however, has very little effect on immune competence, at least for a considerable period. Lymphoid cells require central lymphoid organ programming in order to differentiate appropriately in response to antigen in peripheral lymphoid tissues, but once that programming has been achieved, cells react as mature cells in peripheral tissues for months or years.

2. Radiation acts on the lymphoid cells and bone marrow. Shielding the lymphoid organs from irradiation protects against diminished immune capacity. Radiation damages DNA; thus, cells that are in the process of division or that need to divide to express their immunologic role will be most affected by this exposure.

Chemical and biological immunosuppressive agents include therapeutic agents for autoimmune disease, some of which are also cancer chemotherapeutics. Most anticancer agents have some degree of immunosuppressive activity.

1. Since a role of the immune response is limitation or protection against infectious disease, the result of immunosuppression with any of these drugs or with any other procedure is increased incidence and chronicity of infectious disease. When immunosuppressive agents are used, the patient is more subject to infectious disease and malignancy.

2. Action of immunosuppressive agents

a. Lympholytic agents: The two major types are ionizing radiation and antiserum (i.e., antilymphocyte serum and antithymocyte serum).

b. Lymphocytotoxic agents:

Antimetabolites, such as purine and pyrimidine analogs and folic acid antagonists (methotrexate), interfere with DNA synthesis.

Alkylating agents, such as cyclophosphamide, interfere with cell division by altering guanine so that base pairing errors occur. They also can cross-link the two strands, thus blocking DNA replication.

Antibiotics, such as cyclosporine, exert an inhibitory effect on interleukin-2 action, thus blocking the expansion of the helper/inducer T-cell population. It is particularly effective in suppression graft rejection reactions.

c. Cortisone is immunosuppressive as well as anti-inflammatory. It has the following effects:

- It depresses macrophage chemotaxis and interleukin-1 production.

- It inhibits calcium ion influx into cells.

- It depresses release and/or effect of interleukin-2, lymphotoxin, macrophage migration-inhibition factor (MIF), and macrophage-activating factor (MAF).

- It blocks cleavage of membrane phospholipids, thus lowering prostaglandin and leukotriene levels by inhibiting arachidonic acid release from the membrane.

d. Antibodies: Antibodies that react with lymphoid cells:

If injected into the body, the antibodies against T cells can find all the lymphocytes in the lymph nodes, blood, and other components of the reticuloendothelial system.

Antilymphocyte serum, particularly antithymocyte serum, is most useful in inducing immune deficiency in transplant patients by suppression of all cell-mediated immune responses.

If a performed antibody is injected into an animal, followed by injection of specific antigen, the immune response in the host will be blocked. The injected antibody binds up the antigen and prevents its access to lymphoid tissue. This is the principle through which Rho(D) immunoglobulin (RhoGAM) was developed to combat Rh incompatibility (erythroblastosis fetalis). Antiserum against the immunogen (Rh antigen) will neutralize the antigen through some mechanism (probably by coating it in such a way that it is cleared from the body very rapidly); thus, an immune response is aborted.

B. Immunodefficiency Disorders

In view of the complex nature of the immune response, it is not surprising that a wide array of deficiencies exist, heralded primarily by recurrent infection, chronic infection, unusual (opportunistic) infecting agents, and a poor response to treatment.

Congenital Immunodeficiencies:

1. Bruton’s hypogammaglobulinemia failure of development of B-cell (humoral) immunity. These patients form antibodies very poorly and suffer from repeated bacterial infections.

2. DiGeorge syndrome failure of development of the third and fourth pharyngeal pouches during embryogenesis. These patients have a great deal of trouble with recurrent viral diseases.

Malignancies are potentially immunosuppressive, particularly if they involve lymphoid tissues.

Infections:

1. Measles and certain other viral diseases cause a transient depression in cell-mediated immune responses.

2. Human T-cell lymphotropic virus [(HTLV-III), also known as human immunodeficiency virus (HIV)] infection causes a profound immunosuppression which renders the host susceptible to fatal infections caused by opportunistic pathogens.

3. Specific anergy is seen in lepromatous leprosy and the terminal stages of tuberculosis.

Malnutrition:

1. Cell-mediated immunity appears to be the most sensitive to nutritional deprivation, but humoral immunity, complement, and phagocytic functions are also affected.

Phagocytic cell defects:

1. Quantitative defects. In quantitative defects in Polymorphonuclear leukocytes (neutrophils), referred to as neutropenia or granulocytopenia, the total number of normal, circulating cells is suppressed.

2. Qualitative defects.

a. Chronic granulomatous disease: Granuloma formation occurs in many organs, and it appears to reflect the inability of, first, neutrophils and then tissue macrophages to kill ingested microorganisms.

b. Myeloperoxidase deficiency is an important microbicidal agent contained in normal neutrophils. Hydrogen peroxide is formed in these patients in normal amounts; however, both myeloperoxidase and hydrogen peroxide are necessary for neutrophil killing function.

c. Chediak-Higashi syndrome is a relatively rare disease of humans and of a variety of animals. The patient’s neutrophils contain abnormal, giant lysosomes, which can apparently fuse with the phagosome but which are impaired in their ability to release their contents, resulting in a delayed killing of ingested microorganisms.

d. Job’s syndrome, hyperimmunoglobulinemia E (hyper-IgE) syndrome. Neutrophils demonstrate normal ingestion and killing activity by defective chemotaxis. Serum levels of IgE are extremely high in association with increased specificity for staphylococcal antigens.

e. Lazy leukocyte syndrome is characterized by susceptibility to severe microbial infections, neutropenia, defective chemotactic response by neutrophils, and an abnormal inflammatory response.

B-cell deficiency disorders:

1. Bruton’s X-linked hypogammaglobulinemia. The primary bacterial infections do not induce immunoglobulin synthesis. Cellular immunity is normal in these patients.

2. Transient hypogammaglobulinemia of infancy results when the onset of immunoglobulin synthesis, particularly IgG synthesis, is delayed beyond the norm.

3. Common variable hypogammaglobulinemia (acquired hypogammaglobulinemia) resembles Bruton’s disease except that symptoms first appear when the patient is 20 to 30 years of age.

4. Selective immunoglobulin deficiency (dysgammaglobulinemia) describes a decrease in the serum level of one or more immunoglobulins, but not all immunoglobulins, with normal or increased levels of the others. The most common form of this disorder is selective IgA deficiency.

T-cell deficiency disorders:

1. DiGeorge syndrome (congenital thymic hypoplasia) is due to faulty development of the third and fourth pharyngeal pouches during embryogenesis, with resulting absence or hypoplasia of both the thymus and parathyroid glands. Lymphocytopenia is usual in these patients. T cells are diminished in number.

2. Chronic mucocutaneous candidiasis is a syndrome of skin and mucous membrane infection with Candida albicans, which is associated with a rather unique defect in T-cell immunity. Although the total lymphocyte count appears to be normal, the ability of the T cells to be activated by, or to produce macrophage migration-inhibition factor (MIF) in the presence of Candida antigen is impaired, although their response to other antigens may be normal.

Combined B-cell and T-cell deficiency disorders

Severe combined immunodeficiency disease (SCID) involves a combined defect in both humoral (B-cell) and cell-mediated (T-cell) immunity. Patients usually die within the first or second year of life from viral, bacterial, fungal, or protozoan infection. SCID may be inherited as an X-linked recessive or autosomal recessive disease.

1. Nezelof’s syndrome. There is a marked deficiency of T-cell immunity. B-cell deficiency varies. The antibody response to specific antigens is usually low or absent.

2. Wiskott-Aldrich syndrome comprises a triad of features including thrombocytopenia, which is present at birth; eczema, which usually is present at the age of 1 year; and recurrent pyogenic infection (e.g., with S. pneumoniae, Neisseria meningitidis, or H. influenzae), starting after 5 months of age. There is a variable deficit in T-cell immunity.

3. Ataxia-telangiectasia is an autosomal recessive disease and is characterized by uncoordinated muscle movements (ataxia) and dilatation of small blood vessels in the sclera of the eye (telangiectasia). It is associated with repeated sinopulmonary infections due to various viral and bacterial agents. The neurologic, endocrine, and vascular systems are involved. There is selective IgA deficiency with variable abnormalities affecting other immunoglobulins and, occasionally, an inhibited antibody response to certain antigens. T-cell deficiency is variable.

4. Enzyme deficiencies have been reported to be the cause of at least some degree of combined immunodeficiency. Deficiencies of both adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) are autosomal recessive traits. ADA and PNP are necessary for the purine salvage pathway.

C. Secondary Immunodeficiencies

Measles is an example of a disease that induces immunosuppression. The infection induces a transient suppression of delayed hypersensitivity reactions. Lymphocytic response to antigens and mitogens is reduced. The number of circulating T cells is decreased. Similar effects may be seen following measles immunization.

Leprosy is another infection with associated immunodeficiency. Patients with lepromatous leprosy have an impaired ability to develop delayed hypersensitivity reactions. However, whether immunosuppression leads to or is caused by leprosy is not certain.

Tuberculosis and coccidioidomycosis are other examples. Both impair delayed hypersensitivity reactions.

Acquired immune deficiency syndrome (AIDS) affects primarily, but not exclusively, male homosexuals, intravenous drug abusers, hemophiliacs, and other individuals who receive transfusions. It is caused by a retrovirus, which formerly was referred to as human T-cell lymphotropic virus III (HTLV-III) or lymphadenopathy-associated virus (LAV) but now is designated human immunodeficiency virus (HIV). Patients demonstrate pronounced suppression of the immune system and development of Kaposi’s sarcoma, severe opportunistic infection (e.g., with Pneumocystis carinii, Mycobacterium avium-intracellulare, or Toxoplasma), or both. Marked lymphopenia is associated with a reduction in the level of CD4 cells and resultant reversal of the CD4:CD8 ratio less than 0.5 (normal > 1.5). There is an impaired response of peripheral blood lymphocytes to PHA and specific antigens. Specific antibody production is impaired. The lymphocytes cannot produce the normal amount of interleukin-2, and the activity of natural killer (NK) cells is reduced.

HIV incorporates itself into host cell genome (it lasts for life), attacks and incapacitates the body’s central immune system. Thus the body cannot fight diseases caused by intracellular pathogens or even normally harmless microbes. The HIV multiplies profusely in phagocytic monocytes without killing them and so propagates throughout the body and loads body fluids with virus, induces body to attack itself (autoimmune inactivation of IL-2, cytotoxic humoral antibodies killing lymphocytes, CD8 cells killing CD4 cells), and is antigenically variable.

AIDS has a long incubation period (usually 3 years or longer) and appears to be 100% fatal. HIV probably will cause the greatest pandemic in human history: millions have been infected and are spreading HIV, probably about 2 million in U.S.A. alone; these infected people are carriers and potential sources for life. There is no cure and no vaccine. HIV is transmitted best by blood, probably by infected cells (T cells and monocytes or macrophages).

Reaction of host for infection of his own T cells and macrophages with the transmitted ones (close cell-cell contact which part of recognition/response mechanisms) promotes infection. Initial multiplication of HIV in newly-infected subject results in humoral Ab immune response (a few days after infection) and probably promotes infection by increasing HIV uptake by uninfected macrophages (by specific opsonization). A cell-mediated immunity, probably cytotoxic to infected lymphocytes, kills infected cells and results in temporary control of the infection.

HIV selectively attacks CD4 and macrophages because both have the CD4 antigen on them, and CD4 is the receptor for HIV. Infection of the macrophages also is promoted by antibodies made against HIV and by natural intimate contact between macrophages and CD4 cells in induction processes. HIV kills the CD4 cells directly and by syncytial lysis, kills some of the macrophages but just multiplies profusely to be shed in large numbers from others. The mature/activated macrophage is the most permissive for HIV. In the infected CD4 cell, HIV reverse transcriptase incorporates HIV genes in host cell genome. When the infected CD4 cell becomes activated (e.g., by other antigenic stimulation), in replicating itself it also replicates HIV, which kills it.

CD8 cells can recognize HIV antigen on CD4 cells as foreign, and will kill infected CD4 cells, adding to loss of these cells. HIV glycoprotein in the envelope is homologous to IL-2. Thus, HIV induces production of IL-2-neutralizing autoantibodies. These antibodies plus complement can kill IL-2-bearing cells.

While neutralizing antibodies are made which can block HIV from infecting new T cells, these cannot get at intracellular HIV. Furthermore, HIV changes its surface antigenicity frequently, making previously effective antibodies no longer effective.

HIV causes flu-like symptoms in about 2 weeks after initial infection, then becomes dormant (perhaps in response to antibody and cytotoxic immunity). In a mean time of 5 years later, it emerges again in various disease forms, the most familiar being lymphadenopathy ( AIDS-related complex) AIDS.

AIDS is said to have developed when victim is overrun with opportunistic infections, the most common of which are with Pneumocystis carinii and M. avium. Both of these microorganisms probably are found in everyone but don’t cause disease until the body becomes unable to develop any cell-mediated immunity. HIV infection is detected by primary binding tests, usually ELISA (screening test) and Western blot for antibodies to specific viral envelope antigens (confirmatory test). Anyone with these antibodies can (1) presume to have been infected, (2) be infectious, and (3) be expected to develop one or another of the fatal manifestations of AIDS.

Plasma cell dyscrasias represents a group of diseases characterized by the overproduction of immunoglobulins, or their fragments by a single clone of plasma cells. The protein is called paraprotein. The most important of the plasma cell dyscrasias is multiple myeloma; other notable disorders include Waldenstrom’s macroglobulinemia, benign monoclonal gammopathy, primary amyloidosis, and heavy chain diseases.

Complement deficiencies. Deficiency of complement components and function has been associated with increased susceptibility to infection, autoimmune disease, and other disorders.

1. C1 esterase inhibitor deficiency

2. C1q deficiency

3. C2 and C4 deficiencies

4. C3 deficiencies

5. C5 deficiency

6. C6, C7, and C8 deficiencies

 
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