Immune disorders

Daniel P Stitis, MD

Infantile X-linked Agammaglobulinemia
This hereditary disorder results in a deficit in B cell function with essentially intact T cell function.
Clinical Findings
The diagnosis is based on low IgG levels in serum, an X-linked pattern of heredity, intact cell-mediated immunity, and the absence of plasma cells in biopsy specimens of regional lymph nodes draining the site of recent antigenic stimulation, eg, DPT vaccine.
A. Symptoms and Signs: There are no symptoms during the first 5-6 months of life (probably due to presence of maternal antibody). Thereafter, the infant shows increased susceptibility to pyogenic infections (gram-positive organisms) and Haemophilus in.fluenzae, resulting in recurrent furunculosis, pneumonia, and meningitis. There is normal susceptibility to viral exanthematous infections such as rubella, measles, and chickenpox. Other characteristic findings are chronic sinusitis, bronchiectasis, and arthritis of the large joints similar to rheumatoid arthritis.
B. Laboratory Findings: IgG levels in the serum are less than 200 mg/dL, serum IgA and IgM levels are less than 1% of normal, and isohemagglutinins are low or absent. The Schick test is positive, and antitoxin titers do not rise after vaccination with DPT vaccine. The peripheral lymphocyte count and delayed type hypersensitivity skin tests are normal. There are no B lymphocytes but normal or elevated T lymphocytes in the peripheral blood in most cases.
Treatment
Recurrent bacterial infections can be prevented by the administration of gamma globulin for an indefinite period of time. The gamma globulin is usually administered intramuscularly at a dose of 0.2-0.4 mL/kg. Intravenous gamma globulin is also used at a dose of 100-400 mg/kg given over 2-4 hours as often as weekly in severely ill patients. The need for repeated infusions can be determined by monitoring blood levels of IgG. Although the use of appropriate antibiotics has improved the prognosis, it remains poor.
Thymic Hypoplasia (DiGeorge’s Syndrome)
DiGeorge’s syndrome is due to failure of embryogenesis of the third and fourth pharyngeal pouches. This results in aplasia of the parathyroid and thymus glands. The syndrome presents as a pure T cell functional deficiency with relatively intact B cell function in combination with hypoparathyroidism.
Clinical Findings
A. Symptoms and Signs: The major manifestations are neonatal tetany, hypertelorism, and increased susceptibility to viral, fungal, and bacterial infections. Infections are frequently lethal.
B. Laboratory Findings: Serum immunoglobulin levels are usually normal. Antibody responses may be low or normal, depending on the antigen used for immunization. Reactions to delayed hypersensitivity skin tests are absent, lymphocyte counts are low, and functional T cell assays are abnormal. Serum calcium is reduced, phosphorus is elevated, and parathyroid hormone is absent. Biopsy of lymph nodes shows normal germinal center formation but marked deficits in the thymus-dependent or paracortical areas.
Treatment
Transplantation of fetal thymic tissue has been successful in reversing the deficits in cell-mediated immunity and raising the peripheral lymphocyte count to normal. The thymus-dependent areas of the lymph nodes of transplant recipients are also repopulated. Hypoparathyroidism can usually be managed with oral calcium supplemented with vitamin D or parathyroid hormone. Spontaneous remissions may occur. The prognosis is primarily related to the severity of congenital heart disease.
Severe Combined Immunodeficiency
Both T and B cell function are markedly decreased in this entity, which is inherited in an autosomal recessive or X-linked pattern. A sporadic appearance in families also occurs. Dysostosis and adenosine deaminase deficiency occur in some cases.
Clinical Findings
A. Symptoms and Signs: Increased susceptibility to infection is noted at 3-6 months of age. Death usually occurs within 2 years. In infancy, there is watery diarrhea, usually associated with Salmonella or enteropathic Escherichia coli infections. Pulmonary infections, usually with Pseudomonas and Pneumocystis carinii, are common, as is candidiasis in the mouth and diaper areas. Common viral exanthems such as chickenpox and measles are often lethal.
B. Laboratory Findings: Serum immunoglobulin levels are usually less than 1% of normal, and antibodies do not form in response to vaccinations such as DTP. The peripheral lymphocyte count is less than 2000/1J.L. Decreased delayed hypersensitivity is manifested by lack of skin reactivity to antigens. Lymph node biopsy shows no lymphocytes, plasma cells, or lymphoid follicles.
Treatment
Passive administration of gamma globulin in doses of 100-400 mg/kg intravenously every 1-4 weeks is temporarily effective. An expert in immunodeficiency disorders should be consulted. Bone marrow transplantation has been successful.
Immunodeficiency With Thrombocytopenia & Eczema (Wiskott-Aldrich Syndrome)
This disorder is characterized by eczema, thrombocytopenia, and recurrent bacterial and viral infections. Inheritance is X-linked, and affected individuals rarely survive more than 10 years. There appears to be a combined T and B cell functional deficit. IgM levels are low and isohemagglutinins absent, but IgG and IgA levels are normal. Cell-mediated immunity is impaired. Treatment is symptomatic for infections and thrombocytopenia. Successful bone marrow transplantation has been achieved.
Immunodeficiency with at Axia-Telangiect Asia
Ataxia-telangiectasia begins in infancy with ataxia and choreoathetoid movements. Telangiectasia of the conjunctiva, face, arms, and eyelids is first noted 5-10 years later. Chronic sinusitis and respiratory infections follow, and death due to intercurrent pulmonary infection or lymphoreticular neoplasm occurs in the second or third decade. Approximately 80% of affected individuals lack serum and secretary IgA. In addition, there is a marked deficit in T cell function associated with a hypoplastic or dysplastic thymus gland. The disease is inherited in an autosomal recessive pattern.
Common Variable Immunodeficiency
Onset is in adulthood, with increased susceptibility to pyogenic infections; recurrent sinusitis and pneumonia progressing to bronchiectasis; spruelike syndrome with diarrhea, steatorrhea, malabsorption, and protein-losing enteropathy; and hepatosplenomegaly.
Arthritis of the type associated with congenital hypogammaglobulinemia and autoimmune diseases may occur. Serum IgG levels are usually less than 250 mg/dL; serum IgA and IgM levels are subnormal. Lymph node biopsy shows marked reduction in plasma cells. Noncaseating granulomas are frequently found in the spleen, liver, lungs, or skin.
Suppressor T cells inhibit B cells from producing, antibody-forming cells in certain cases of adult-onset hypogammaglobulinemia. The absolute B cell count in the peripheral blood in these cases is normal. Therapy at present is similar to that of congenital hypogammaglobulinemia, with 100-400 mg/kg of intravenous gamma globulin at about monthly intervals.
Selective Immunoglobulln Deficiency
Absence of serum IgA with normal levels of IgG and IgM is found in a small percentage of normal individuals. Some cases of IgA deficiency may spontaneously remit. The associated deficiency of the IgG2 subclass is often associated with infections. Occasionally, a spruelike syndrome with steatorrhea has been associated with an isolated IgA deficit. Treatment with commercial gamma globulin is ineffective, since IgA and IgM are not present in this preparation. Frequent infusions of plasma (containing IgA) are hazardous, since anti-IgA antibodies may develop, resulting in systemic anaphylaxis or serum sickness.
Acquired Immunodeficiency Syndrome (Aids)
AIDS is an example of a hitherto unrecognized farm of immunodeficiency in which a chronic retroviral infection with HIV-human immunodeficiency virus-in a susceptible host produces severe, life-threatening T cell defects. In addition to reduction of CD4 (T helper cells), there is an increase in CD8 (T suppressor cells), most of which have a cytotoxic phenotype.
B cell function is altered so that many infected individuals have marked hypergammaglobulinemia, and AIDS patients fail to respond normally to antigens when immunized. Autoantibodies to T cells and circulating immune complexes are present. Most infected individuals progress from health to ARC (AIDS-related complex) to AIDS over several years. The immunologic determinants of the clinical fate of persons infected with HIV are unknown.
In AIDS, immunologic tests reveal a severe deficiency of T lymphocyte function and number, with little alteration in B lymphocyte numbers. Patients are frequently anergic. In vitro tests of peripheral blood T cell function such as proliferative responses to antigens and mitogens are markedly reduced or absent.
The absolute lymphocyte count is severely decreased (frequently < 500 cells/fLL), and the ratio of helper to suppressor/cytotoxic T cells is considerably lower than normal. The change in the latter ratio is due to a greater reduction in the absolute number of helper T cells in the peripheral blood as compared to suppressor/cytotoxic cells. The immunologic changes that occur in asymptomatic HIV sero-positive individuals or those with ARC are usually not as marked as those in AIDS patients.
Secondary Immunodeficiency
Deficiencies in T cell immunity, antibody immunity, or both have been associated with many diseases. Two examples of altered immunity secondary to underlying disease are discussed below.
Immunodeficiency Associated With Sarcoidosis
The immunodeficiency associated with sarcoidosis is characterized by a partial deficit in T cell function with intact or increased B cell function. Patients with sarcoidosis often are relatively nonreactive to intradermal injections of common antigens. However, complete lack of skin reactivity is infrequent. A positive reaction to purified protein derivative is usually noted during active infection with Mycobacterium tuberculosis. Serum immunoglobulin levels are normal or high, and specific antibody formation is generally normal.
Immunodeficiency Associated With Hodgkin’s Disease
A moderate to severe deficit in T cell function with intact B cell function is frequently found in Hodgkin’s disease.  Only 10-20% of patients with Hodgkin’s disease show skin reactivity to common antigens, as compared to 70-90% of controls. Many patients show depressed responses to in vitro stimulation of peripheral blood lymphocytes with phytohemagglutinin. Serum immunoglobulins are normal, and specific antibody formation is intact except in agonal cases.  The clinical significance of depressed cell-mediated immunity in Hodgkin’s disease is difficult to evaluate, since most patients are
treated with potent immunosuppressive agents. Nevertheless,
frequent infections with herpes zoster and Cryptococcus are probably related to immunodeficiency associated with the underlying disease.

 

 

Immune disorders

Daniel P Stitis, MD Infantile X-linked Agammaglobulinemia This hereditary disorder results in a deficit in B cell function with essentially intact T cell function. Clinical Findings The diagnosis is based on low IgG levels in serum, an X-linked pattern of heredity, intact cell-mediated immunity, and the absence of plasma cells in biopsy specimens of regional lymph nodes draining the site of recent antigenic stimulation, eg, DPT vaccine. A. Symptoms and Signs: There are no symptoms during the first 5-6 months of life (probably due to presence of maternal antibody). Thereafter, the infant shows increased susceptibility to pyogenic infections (gram-positive organisms) and Haemophilus in.fluenzae, resulting in recurrent furunculosis, pneumonia, and meningitis. There is normal susceptibility to viral exanthematous infections such as rubella, measles, and chickenpox. Other characteristic findings are chronic sinusitis, bronchiectasis, and arthritis of the large joints similar to rheumatoid arthritis. B. Laboratory Findings: IgG levels in the serum are less than 200 mg/dL, serum IgA and IgM levels are less than 1% of normal, and isohemagglutinins are low or absent. The Schick test is positive, and antitoxin titers do not rise after vaccination with DPT vaccine. The peripheral lymphocyte count and delayed type hypersensitivity skin tests are normal. There are no B lymphocytes but normal or elevated T lymphocytes in the peripheral blood in most cases. Treatment Recurrent bacterial infections can be prevented by the administration of gamma globulin for an indefinite period of time. The gamma globulin is usually administered intramuscularly at a dose of 0.2-0.4 mL/kg. Intravenous gamma globulin is also used at a dose of 100-400 mg/kg given over 2-4 hours as often as weekly in severely ill patients. The need for repeated infusions can be determined by monitoring blood levels of IgG. Although the use of appropriate antibiotics has improved the prognosis, it remains poor. Thymic Hypoplasia (DiGeorges Syndrome) DiGeorges syndrome is due to failure of embryogenesis of the third and fourth pharyngeal pouches. This results in aplasia of the parathyroid and thymus glands. The syndrome presents as a pure T cell functional deficiency with relatively intact B cell function in combination with hypoparathyroidism. Clinical Findings A. Symptoms and Signs: The major manifestations are neonatal tetany, hypertelorism, and increased susceptibility to viral, fungal, and bacterial infections. Infections are frequently lethal. B. Laboratory Findings: Serum immunoglobulin levels are usually normal. Antibody responses may be low or normal, depending on the antigen used for immunization. Reactions to delayed hypersensitivity skin tests are absent, lymphocyte counts are low, and functional T cell assays are abnormal. Serum calcium is reduced, phosphorus is elevated, and parathyroid hormone is absent. Biopsy of lymph nodes shows normal germinal center formation but marked deficits in the thymus-dependent or paracortical areas. Treatment Transplantation of fetal thymic tissue has been successful in reversing the deficits in cell-mediated immunity and raising the peripheral lymphocyte count to normal. The thymus-dependent areas of the lymph nodes of transplant recipients are also repopulated. Hypoparathyroidism can usually be managed with oral calcium supplemented with vitamin D or parathyroid hormone. Spontaneous remissions may occur. The prognosis is primarily related to the severity of congenital heart disease. Severe Combined Immunodeficiency Both T and B cell function are markedly decreased in this entity, which is inherited in an autosomal recessive or X-linked pattern. A sporadic appearance in families also occurs. Dysostosis and adenosine deaminase deficiency occur in some cases. Clinical Findings A. Symptoms and Signs: Increased susceptibility to infection is noted at 3-6 months of age. Death usually occurs within 2 years. In infancy, there is watery diarrhea, usually associated with Salmonella or enteropathic Escherichia coli infections. Pulmonary infections, usually with Pseudomonas and Pneumocystis carinii, are common, as is candidiasis in the mouth and diaper areas. Common viral exanthems such as chickenpox and measles are often lethal. B. Laboratory Findings: Serum immunoglobulin levels are usually less than 1% of normal, and antibodies do not form in response to vaccinations such as DTP. The peripheral lymphocyte count is less than 2000/1J.L. Decreased delayed hypersensitivity is manifested by lack of skin reactivity to antigens. Lymph node biopsy shows no lymphocytes, plasma cells, or lymphoid follicles. Treatment Passive administration of gamma globulin in doses of 100-400 mg/kg intravenously every 1-4 weeks is temporarily effective. An expert in immunodeficiency disorders should be consulted. Bone marrow transplantation has been successful. Immunodeficiency With Thrombocytopenia Eczema (Wiskott-Aldrich Syndrome) This disorder is characterized by eczema, thrombocytopenia, and recurrent bacterial and viral infections. Inheritance is X-linked, and affected individuals rarely survive more than 10 years. There appears to be a combined T and B cell functional deficit. IgM levels are low and isohemagglutinins absent, but IgG and IgA levels are normal. Cell-mediated immunity is impaired. Treatment is symptomatic for infections and thrombocytopenia. Successful bone marrow transplantation has been achieved. Immunodeficiency with at Axia-Telangiect Asia Ataxia-telangiectasia begins in infancy with ataxia and choreoathetoid movements. Telangiectasia of the conjunctiva, face, arms, and eyelids is first noted 5-10 years later. Chronic sinusitis and respiratory infections follow, and death due to intercurrent pulmonary infection or lymphoreticular neoplasm occurs in the second or third decade. Approximately 80% of affected individuals lack serum and secretary IgA. In addition, there is a marked deficit in T cell function associated with a hypoplastic or dysplastic thymus gland. The disease is inherited in an autosomal recessive pattern. Common Variable Immunodeficiency Onset is in adulthood, with increased susceptibility to pyogenic infections; recurrent sinusitis and pneumonia progressing to bronchiectasis; spruelike syndrome with diarrhea, steatorrhea, malabsorption, and protein-losing enteropathy; and hepatosplenomegaly. Arthritis of the type associated with congenital hypogammaglobulinemia and autoimmune diseases may occur. Serum IgG levels are usually less than 250 mg/dL; serum IgA and IgM levels are subnormal. Lymph node biopsy shows marked reduction in plasma cells. Noncaseating granulomas are frequently found in the spleen, liver, lungs, or skin. Suppressor T cells inhibit B cells from producing, antibody-forming cells in certain cases of adult-onset hypogammaglobulinemia. The absolute B cell count in the peripheral blood in these cases is normal. Therapy at present is similar to that of congenital hypogammaglobulinemia, with 100-400 mg/kg of intravenous gamma globulin at about monthly intervals. Selective Immunoglobulln Deficiency Absence of serum IgA with normal levels of IgG and IgM is found in a small percentage of normal individuals. Some cases of IgA deficiency may spontaneously remit. The associated deficiency of the IgG2 subclass is often associated with infections. Occasionally, a spruelike syndrome with steatorrhea has been associated with an isolated IgA deficit. Treatment with commercial gamma globulin is ineffective, since IgA and IgM are not present in this preparation. Frequent infusions of plasma (containing IgA) are hazardous, since anti-IgA antibodies may develop, resulting in systemic anaphylaxis or serum sickness. Acquired Immunodeficiency Syndrome (Aids) AIDS is an example of a hitherto unrecognized farm of immunodeficiency in which a chronic retroviral infection with HIV-human immunodeficiency virus-in a susceptible host produces severe, life-threatening T cell defects. In addition to reduction of CD4 (T helper cells), there is an increase in CD8 (T suppressor cells), most of which have a cytotoxic phenotype. B cell function is altered so that many infected individuals have marked hypergammaglobulinemia, and AIDS patients fail to respond normally to antigens when immunized. Autoantibodies to T cells and circulating immune complexes are present. Most infected individuals progress from health to ARC (AIDS-related complex) to AIDS over several years. The immunologic determinants of the clinical fate of persons infected with HIV are unknown. In AIDS, immunologic tests reveal a severe deficiency of T lymphocyte function and number, with little alteration in B lymphocyte numbers. Patients are frequently anergic. In vitro tests of peripheral blood T cell function such as proliferative responses to antigens and mitogens are markedly reduced or absent. The absolute lymphocyte count is severely decreased (frequently 500 cells/fLL), and the ratio of helper to suppressor/cytotoxic T cells is considerably lower than normal. The change in the latter ratio is due to a greater reduction in the absolute number of helper T cells in the peripheral blood as compared to suppressor/cytotoxic cells. The immunologic changes that occur in asymptomatic HIV sero-positive individuals or those with ARC are usually not as marked as those in AIDS patients. Secondary Immunodeficiency Deficiencies in T cell immunity, antibody immunity, or both have been associated with many diseases. Two examples of altered immunity secondary to underlying disease are discussed below. Immunodeficiency Associated With Sarcoidosis The immunodeficiency associated with sarcoidosis is characterized by a partial deficit in T cell function with intact or increased B cell function. Patients with sarcoidosis often are relatively nonreactive to intradermal injections of common antigens. However, complete lack of skin reactivity is infrequent. A positive reaction to purified protein derivative is usually noted during active infection with Mycobacterium tuberculosis. Serum immunoglobulin levels are normal or high, and specific antibody formation is generally normal. Immunodeficiency Associated With Hodgkins Disease A moderate to severe deficit in T cell function with intact B cell function is frequently found in Hodgkins disease. Only 10-20% of patients with Hodgkins disease show skin reactivity to common antigens, as compared to 70-90% of controls. Many patients show depressed responses to in vitro stimulation of peripheral blood lymphocytes with phytohemagglutinin. Serum immunoglobulins are normal, and specific antibody formation is intact except in agonal cases. The clinical significance of depressed cell-mediated immunity in Hodgkins disease is difficult to evaluate, since most patients are treated with potent immunosuppressive agents. Nevertheless, frequent infections with herpes zoster and Cryptococcus are probably related to immunodeficiency associated with the underlying disease.