Humoral immunity, defects

Low levels or absence of adenosine deaminase (ADA) is associated with one form of severe combined immunodeficiency disease (SCID) characterized by B-andT-lymphocyte dysfunction due to toxic effects of deoxyadenosine (HI9). Most patients present as infants with failure to thrive, repeated infections, severe lymphopenia, and defective cellular and humoral immunity. Disease severity is correlated with the degree of deoxyadenosine nucleotide pool expansion and inactivation of S-adenosylhomocysteine hydrolase in red blood cells. Up to now, more than 40 mutations have been identified (A4, H20, S5, S6). The majority of the basic molecular defects underlying ADA deficiency of all clinical phenotypes are missense mutations. Nonsense mutations, deletions ranging from very large to single nucleotides, and splicing mutations have also been reported. It is likely that severe... 

Kerkvliet, N. and Brauner, J., Mechanisms of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD)-induced humoral immune suppression Evidence of primary defect in T cell regulation, Tox. Appl. Pharmacol., 87, 18, 1987. 

The marked decrease of the serum IgM in patients with Burkitt s lymphoma have been confirmed by Ziegler et al. (Zl) in East Africa, who noticed an impairment of the primary antibody response and low serum IgM levels in untreated patients with Burkitt s lymphoma, but not in patients in remission. They postulated a defect in humoral immunity possibly to impaired IgM synthesis. 

Primary immunodeficiency diseases (PIDs) are defects of the immune system that are due to genetic abnormalities or some failure in normal embryological development. They are usually apparent at birth or develop shortly thereafter. Approximately 70 PIDs have been described, including those specihc for humoral immunity (e.g., X-linked agammaglobulinemia, immune globulin [Ig] A dehciency), cellular immunity (e.g., DiGeorge s syndrome), or both (e.g., severe combined immunodehciency syndrome). 

Although the a-chain is very important (and fundamental for the appearance of high-affinity IL-2R), the y-chain has a key role based on its molecular pluripresence (found in IL-4, IL-7, IL-9, and IL-15 receptors but possibly not the IL-13 receptor), constitutive expression by lymphoid cells, and genetic defect in the immune response. The latter results in X-linked severe combined immunodeficiency (XSCID) characterized by profoundly diminished ceU-mediated and humoral immunity. 

Patients with ADA deficiency lack both T- and B-lymphocyte-mediated functions, namely, cellular and humoral immunity, respectively, and exhibit a severe combined immunodeficiency (SCID) disorder. Other genetic defects can cause SCID (Chapter 35), but ADA deficiency is responsible for about one-third of patients who have SCID. PNP deficiency is associated only with T-lymphocyte dysfunction. 

Diabetic patients typically have normal humoral immunity, normal levels of immunoglobulins, and normal antibody responses. Patients with diabetes, however, have impaired phagocytosis and intracellular microbicidal function as compared with nondiabetics this may be related to angiopathy and low tissue levels of oxygen. These defects in cell-mediated immunity make patients with diabetes more susceptible to certain types of infection and impair the patients ability to heal wounds adequately. ... 

Recipients of HSCT remain at high risk for infection after bone marrow engraftment has occurred. Significant defects in neutrophil function and cell-mediated and humoral immunity, persisting for several months after transplantation, predispose patients to infectious complications. Acute and chronic GVHD also result in prolonged periods of immunosuppression and increased infection rates. 

The patient with HIV infection requires special consideration. Responses to live and killed antigens generally are suboptimal and decrease as the disease progresses because HTV produces defects in cell-mediated immunity and humoral immunity. 

Two different immunodeficiency diseases are now known to result from defects in purine catabolic reactions. In adenosine deaminase deficiency, large concentrations of dATP inhibit ribonucleotide reductase. Consequently, DNA synthe- i= sis is depressed. For reasons that are not yet clear, this metabolic distortion is observed primarily in the T and B lymphocytes. ( / lymphocytes, or T cells, bear antibody-like molecules on their surfaces. They bind to and destroy foreign cells in a process referred to as cellular immunity. B lymphocytes, or B cells, produce antibodies that bind to foreign substances, thereby initiating their destruction by other immune system cells. The production of antibodies by B cells is referred to as the humoral immune response.) Children with adenosine deaminase deficiency usually die before the age of two because of massive infections. 

Complement system. A group of serum proteins with the capacity to interact with each other when activated. The chain reaction of the activated complement components results in formation of a lytic complex and several biologically active peptides of low molecular weight (anaphylatoxins). The system can be activated by antigen-antibody complexes (classical pathway) and by other components, e.g. bacteria (alternative pathway). As an effector mechanism of the humoral immune response, the activated complement system facilitates opsonization, phagocytosis, and lysis of cellular antigens. Some defects in components of complement are associated with autoimmune diseases (see complement deficiency). 

Ma CS, Hare NJ, Nichols KE et al 2005 Impaired humoral immunity in X-linked lymphopro-liferative disease is associated with defective IL-10 production by CD4-I- T cells. J Clin Invest 115 1049-1059... 

Among the four Jak kinases, Jak-1, Jak-2, Jak-3, and Tyk-2, the yc users all signal via Jak-1 and Jak-3 [30, 31]. This could be explained by the ability of Jak-1 to associate with the chain conferring the specificity for each receptor, namely 1L-2R3 [32, 33], IL-4Ra [34], IL-7Ra [35], and IL-9Ra [36], and probably lL-21Ra [37], whereas Jak-3 associates primarily with yc [33, 35]. The importance of the yc was demonstrated by the discovery that mutations in yc cause X-linked severe combined immunodeficiency (SCID) [30, 38], also named the bubble boy disease. In this disease, both cellular and humoral immunity are defective. In fact, T and NK cells do not develop and even if B cells are present, they are nonfunctional [30, 38]. Interestingly, mutations in Jak-3 were found to cause an autosomal recessive form of SCID [39] and the essential role of Jak-3 in lymphoid development was established [40]. This clearly demonstrated the important role of the Jak-STAT signaling pathway. 

Undoubtedly, both cellular and humoral immune responses are important to recovery from smallpox. The inability of poxviruses to persist stably within the host cell accounts for their infections being relatively short-lived, without establishment of a latent infection. The importance of cellular immunity in recovery from infection has been demonstrated with other poxviruses,39 and the same is generally assumed with variola. Vaccination experiences demonstrated the rare but terrible consequence of vaccinia necrosum in persons with defects of cellular immunity. Early presentation on the host cell membrane of virus-encoded proteins provides means for immune recognition.40 It has been demonstrated that both antibody-dependent cellular cytotoxicity41 and heterogeneous cluster of differentiation (CD) 4+ cytotoxic T-lymphocyte clones42 are induced in response to vaccinia infection, and some immunodominant B-cell epitopes have been defined in both mice and vaccinated humans.43 The relatively large size of poxvirus polypeptides facilitates their rec-... 

A study in 6 healthy subjects found that a single dose of ecstasy produced a time-dependent immune dysfunction. Ecstasy impaired CD4 T-cell function, which is responsible for cellular immunity. Alcohol alone may produce a decrease in T-helper cells and in B lymphocytes, which are responsible for humoral immunity. Concurrent ecstasy and alcohol increased the suppressive effect of ecstasy on CD4 T-cells and increased natural killer cells. It was suggested that the transient defect in immunological homoeostasis could have clinical consequences such as increased susceptibility to infectious diseases. More study is needed. 

Gatner, E. M. S., and Anderson, R., 1980, An in vitro assessment of cellular and humoral immune function in pulmonary tuberculosis Correction of defective neutrophil motility by ascorbate, le-vamisole, metoprolol and propranolol, Clin. Exp. Immunol. 40 372. 

PKC activity is required for normal immune functioning. In mouse studies, PKCP null mice were found to have deficiencies in B-cell functioning, impaired humoral immunity (Leitges et al, 1996), mast cell degranulation, and interleukin-6 production (Nechushtan et al, 2000). Also, PKC0 null mice were found to have defects in adult T-cell signaling, and particularly in T-cell... 

This chapter is concerned only with the primary defects in the cellular or humoral immune response. Thus, all hypercatabolic states or those due to exogenous agents, such as irradiation or drugs, are excluded as are im-munodeficient states secondary to malignant processes. The primary immunodeficiencies are categorized in the accompanying tabled... 

Aboko-Cole and Lee (1974) found increased parasitemias in folate deficient rats infected with Trypanosoma lewisi. The deficient animals had increased parasite levels in their blood compared to control animals and remained infected for longer periods of time. The results of studies on immune status in a number of species point to defective cell mediated immune function and a possible reduction in humoral immunity as well. 

A continuation of this line of studies for 6 days to 23 weeks at 300 ppm showed continued decreases in numbers of mature B- and T-lymphocytes produced in the bone marrow, spleen, and thymus (Rozen and Snyder 1985). Abnormalities of humoral and cell-mediated immune responses following benzene exposure are presumably caused by a defect in the lymphoid stem cell precursors of both T- and B-lymphocytes. Bone marrow cellularity increased 3-fold, and the number of thymic T-cells increased 15-fold in benzene-exposed mice between the 6th and the 30th exposure. No corresponding increase in splenic cells was noted. The marked increase in the numbers of cells in bone marrow and thymus was interpreted by the authors to indicate a compensatory proliferation in these cell lines in response to... 

Immune defense depends on four complex, interactive systems cell-mediated immunity (T lymphocytes) humoral antibodies (immunoglobulins) the phagocytic system and the complement system. The last two systems are nonspecific in that they have no immunological memory for the antigen. Only the second and fourth systems are composed of plasma proteins. Immunodeficiency states characterized by recurrent infections may be the result of a defect in any one of these systems or combinations thereof. 

In a minority of patients there is a clear picture of long-standing antibody deficiency preceding the development of lymphoid neoplasia. It seems that the humoral defect results in overstimulation of the cellular mechanisms of immunity to a degree increasing the risk of mutation. Evidence that immunoglobulin deficiency can itself sometimes be primary to lymphoid neoplasia has been reviewed elsewhere (F12). 

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