Phagocyte deficiencies include (a) chronic granulomatous disease, (b) Chediak–Higashi syndrome, (c) Job’s syndrome, (d) leukocyte adhesion deficiency, (e) myeloperoxidase defi- ciency, and ( f ) cyclic neutropenia.
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Chronic granulomatous disease
Chronic granulomatous disease (CGD) is a disorder that is inherited as an X-linked trait in two-thirds of the cases and as an autosomal recessive trait in the remaining one-third.
Clinical manifestations are usually apparent before the end of the 2nd year of life. This is a condition associated with defi- ciency of an enzyme NADPH oxidase. This enzyme deficiency causes neutrophils and monocytes to have decreased consump- tion of oxygen and diminished glucose utilization by the hex- ose monophosphate shunt. Although neutrophils phagocytose microorganisms, they do not form superoxide and other oxy- gen intermediates that usually constitute the respiratory burst.
All of these lead to decreased intracellular killing of bacteria and fungi. Thus, these individuals have an increased suscepti- bility to infection with microorganisms that normally are of relatively low virulence. These include Aspergillus, Serratia marc- escens, and Staphylococcus epidermidis.
Patients with CGD may have hepatosplenomegaly, pneu- monia, osteomyelitis, abscesses, and draining lymph nodes.
The quantitative nitroblue tetrazolium (NBT) test and the quantitative killing curve are both employed to confirm the diagnosis of CGD. Therapy includes interferon gamma, antibiotics, and surgical drainage of abscesses.
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Chediak–Higashi syndrome
It is a childhood disorder with an autosomal recessive mode of inheritance. The condition is identified by the presence of large lysozomal granules in leukocytes that are very stable and undergo slow degranulation. The large cytoplasmic granular inclusions that appear in white blood cells may also be observed in blood platelets and can be seen by regular light microscopy in peripheral blood smears. The condition is characterized by a defective neutrophil chemotaxis and an altered ability of the cells to kill ingested microorganisms. The majority of affected individuals die during childhood, although occasional cases may live longer.
There is no effective therapy other than the administration of antibiotics for treatment of the infecting microorganisms.
High doses of ascorbic acid have been shown to restore normal chemotaxis, bactericidal activity, and degranulation.
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Job’s syndrome
Job’s syndrome is caused by failure of helper T cells to produce gamma interferon, which in turn reduces the ability of mac- rophages to kill bacteria. This results in an increased produc- tion of Th-2 and consequently an increased production of IgE.
All these in turn cause more production of histamine that prevents certain components of inflammatory reaction and also inhibits chemotaxis. Therefore, the patient with this syndrome suffers repeatedly from staphylococcal abscesses as well as eczema with a high level of IgE.
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Leukocyte adhesion deficiency
It is an autosomal recessive disease caused by mutation in the gene encoding the B chain of an integrin that mediates adhesion of leukocytes to microbes. This causes poor adhe- sion of neutrophils to endothelial surfaces; hence phagocytosis of bacteria is inadequate.
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Cyclic neutropenia
It is an autosomal dominant disease in which there is a mutation in the gene encoding neutrophil esterase, an enzyme produced by neutrophils. The disease is characterized by a very low neutrophil count, less than 200/L for 3–6 days of a 21-day cycle. The patients are susceptible to life-threatening bacterial infections during these 3–6 days of low neutrophil count but not when neutrophil counts are normal.
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Myeloperoxidase deficiency
It is a disease associated with deficiency of an enzyme myeloper- oxidase, which is essential for the production of hypochlorite, a microbicidal agent. The deficiency of this enzyme is fre- quently seen but has little clinical importance. This is because other intracellular killing mechanisms of leukocytes are intact.
S ection II Chapter 18
IMMUNODEFICIENCY
147 Secondary Immunodeficiencies
Secondary immunodeficiencies occur secondary to numerous diseases or conditions, or as a consequence of therapeutic mea- sures that depress the immune system. Most immunodeficient patients have secondary forms of immunodeficiency, caused by either pathological conditions that affect the immune system or the administration of therapeutic compounds with immunosuppres- sive effects. By far, the most common secondary immunodeficiency is acquired immunodeficiency syndrome (or AIDS), which results from infection with the human immunodeficiency virus (HIV).
Secondary immunodeficiencies are more common than primary immunodeficiencies and include AIDS, chemotherapy by immunosuppressive drugs (e.g., corticosteroids and nonsteroidal anti-inflammatory drugs), psychological depression, burns, radiation, Alzheimer’s disease, celiac disease, sarcoidosis, lymphoproliferative disease, Waldenstrom’s macroglobulinemia, multiple myeloma, aplastic anemia, sickle cell disease, malnutrition, aging, neoplasia, diabetes mellitus, and numerous other condi- tions. Secondary immunodeficiencies may be categorized as (a) B-cell deficiencies, (b) T-cell deficiencies, (c) complement deficien- cies, and (d) phagocytic deficiencies as follows:
B-Cell Deficiencies
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Common variable hypogammaglobulinemia
This condition is caused due to a defective T-cell signaling resulting in failure to produce IgG in the body. This occurs in persons between the ages of 13 and 35 years. In this condi- tion, the number of B cells is normal, but the ability to pro- duce IgG and other immunoglobulins is greatly reduced. The cell-mediated immunity is normal. Patients with this condition are highly susceptible to infections caused by S. pneumoniae, H. influenzae, and other pyogenic bacteria. Administration of intravenous gamma globulin reduces the infections caused by these bacteria.
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Malnutrition
In malnutrition, the synthesis of IgG is reduced due to low sup- ply of amino acids. People with malnutrition, hence, are sus- ceptible to infection by pyogenic bacteria.
T-Cell Deficiencies
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Acquired immunodeficiency syndrome (AIDS)
Patients with AIDS caused by HIV are highly susceptible to infection by many opportunistic pathogens including bac- teria, viruses, fungi, and parasites. This is attributed to the loss of helper T-cell activity. The virus specifically infects and kills the cells bearing CD4 surface receptors. The immu- nity is highly suppressed, and failure of immune surveil- lance leads to a high incidence of tumors. For detail, refer Chapter 68.
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Measles
T-cell function is altered, but immunoglobulins are normal in patients suffering from measles. Patients show a temporary suppression of delayed hypersensitivity.
Complement Deficiencies
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Liver failure
The synthesis of complement proteins is very much reduced in chronic hepatitis B or C and in liver failure caused by alcoholic cirrhosis. Hence, these patients are highly susceptible to infection by pyogenic bacteria.
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Malnutrition
In severe malnutrition, the synthesis of complement proteins by liver is reduced due to low supply of amino acids. Therefore, people with malnutrition are susceptible to infection by pyo- genic bacteria.
Phagocyte Deficiencies
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Neutropenia
The condition is characterized by a low neutrophil count (less than 500/L), caused commonly by cytotoxic drugs, such as those used in cancer therapy. The patients are susceptible to severe bacterial infections caused by pyogenic bacteria, such as S. aureus and S. pneumoniae. Immunodeficiency diseases have been summarized in Table 18-1.
Disease Specific deficiency Molecular defect
B-cell defects
X-linked agammaglobulinemia Absence of B cells, very low IgG levels Mutant tyrosine kinase
Selective IgA deficiency Very low IgA levels Failure of heavy-chain gene switching
Transient hypogammaglobulinemia of infants Delay in initiation of IgG synthesis
Common variable immunodeficiency Total Ig is less, inability of B cells to differentiate Immunodeficiency with hyper-IgM Low IgA and IgG, elevated IgM
Transcobalamin II deficiency Metabolic defects of vitamin B12 deficiency TABLE 18-1 Immunodeficiency syndromes
(Continued)
S ection II Chapter 18
148
IMMUNOLOGYDisease Specific deficiency Molecular defect
T-cell defects
Thymic aplasia (DiGeorge syndrome) Absence of T cells Defective development of pharyngeal pouches Chronic mucocutaneous candidiasis Deficient T-cell response to Candida Unknown
Purine nucleoside phosphorylase (PNP) deficiency
PNP deficiency Autosomal recessive
Both B- and T-cell defects
Nezelof syndrome Deficient T-cell and B-cell immunity
Ataxia telangiectasia Lack of serum and secretory IgA, IgE Autosomal recessive
Wiskott–Aldrich syndrome Depressed cell-mediated immunity, serum IgM X-linked disease
Severe combined immunodeficiency Deficiency of both T cell and B cell Defective IL-2 receptor, kinases, recombinases Immunodeficiency with thymoma Impaired cell-mediated immunity, thymic tumor,
agammaglobulinemia Complement disorders
Hereditary angioedema Deficiency of C1 protease inhibitor Excess C3a, C4a, and C5a generated
Complement component deficiencies Insufficient C3, C6, C7, C8 Unknown
Disorders of phagocytosis
Chronic granulomatous disease Defective bactericidal activity Deficient NADPH oxidase activity Myeloperoxidase deficiency Leukocytes have reduced myeloperoxidase
Chediak–Higashi syndrome Inclusions in leukocytes, diminished phagocytic activity
Leukocyte G6PD deficiency Deficient G6PD in leukocytes TABLE 18-1 Immunodeficiency syndromes (Continued)
Mycobacterium Leprae
43
Hypersensitivity
19
Introduction
Hypersensitivity reaction denotes an immune response result- ing in exaggerated or inappropriate reactions harmful to host.
It is a harmful immune response in which tissue damage is induced by exaggerated or inappropriate immune responses in a sensitized individual on re-exposure to the same antigen. Both the humoral and cell-mediated arms of the immune response may participate in hypersensitivity reactions.
Hypersensitivity essentially has two components. First prim- ing dose (first dose) of antigen is essential, which is required to prime the immune system, followed by a shocking dose (second dose) of the same antigen that results in the injurious consequences.
Depending on the time taken for the reactions and the mechanisms that cause the tissue damage, hypersensitivity has been broadly classified into immediate type and delayed type.
In the former, the response is seen within minutes or hours after exposure to the antigen and in the latter, the process takes days together to manifest as symptoms.
Prince of Monaco first observed the deleterious effects of jel- lyfish on bathers. Subsequently, Portier and Richet (1906) sug- gested a toxin to be responsible for these effects and coined the term “anaphylaxis”.
Gell and Coombs (1963) classified hypersensitivity reac- tions into four categories based on the time elapsed from expo- sure of antigen to the reaction and the arm of immune system involved. Types I, II, and III are antibody-mediated and are known as immediate hypersensitivity reactions, while type IV is cell-mediated (i.e., mediated by cell-mediated immunity) and is known as delayed hypersensitivity reactions.
Type V hypersensitivity reaction has been described later.
It is called stimulatory type reaction and is a modification of type II hypersensitivity reaction.
Differences between immediate and delayed hypersensitivi- ties have been summarized in Table 19-1.