Defects lymphocytes

Fong AM, Premont RT, Richardson RM, Yu YR, Lefkowitz RJ, Patel DD (2002) Defective lymphocyte chemotaxis in beta-arrestin2- and GRK6-deficient mice. Proc Natl Acad Sci USA 99 7478-7483... 

Straus, S. E., and Leirardo, M. J., 1999, Inherited human Caspase 10 mutations underhe defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoprohferative syndrome type II. Cell 98 47-58. 

Fong, A.M., Premont, R.T., Richardson, R.M., Yu, Y.R., Lefkowitz, R.J., and PateL D.D. (2002) Defective lymphocyte chemotaxis in heta-arrestin .- and GRK6-defident mice. Proceedings cf die National Academy of Sdenc of the United States cf America, 99, 7478-7483. 

Immunodeficiency disease A disease of impaired immunity caused by lack of lymphocytes, defective lymphocytes, or destructive lymphocytes. 

Primary immunodeficiencies are uncommon, and may occur in 1 in 10,000 individuals (6). Many primary immunodeficiencies are hereditary and congenital, and first appear in infants and children. Primary immunodeficiencies are classified into four main groups (7) relating to the lymphocytes (B-ceUs, T-ceUs, or both), phagocytes, or the complement cascade (8). Primary deficiency diseases result from B-ceU defects in 50% of cases, from T-ceU defects in ca 10%, and from combined B- and T-ceU defects in ca 20%. Phagocytic disorders account for 18% and complement defects occur in 2% of all cases. 

Lymphocytes are specialized white blood cells that play a crucial role in an immune response.They can be T lymphocytes, which can directly target and destroy defective cells, or B lymphocytes, which produce antibodies directed against specific antigens. Both T and B lymphocytes produce a variety of cytokines to augment and amplify the immune response. 

NF-kB regulates both innate and adaptive immune responses ( immune defense) [2]. Understanding the function of NF-kB in the development, maintenance, and activation of cells from the immune system (including hematopoietic cells, macrophages, dendritic cells, B and T lymphocytes) has greatly benefited from the analysis of knockout mice in which individual NF-kB family members were defective. 

This complex contains 11 polypeptide subunits of which only one is encoded by mtDNA. Defects of complex III are relatively uncommon and clinical presentations vary. Fatal infantile encephalomyopathies have been described in which severe neonatal lactic acidosis and hypotonia are present along with generalized amino aciduria, a Fanconi syndrome of renal insufficiency and eventual coma and death. Muscle biopsy findings may be uninformative since abnormal mitochondrial distribution is not seen, i.e., there are no ragged-red fibers. Other patients present with pure myopathy in later life and the existence of tissue-specific subunits in complex III has been suggested since one of these patients was shown to have normal complex 111 activity in lymphocytes and fibroblasts. 

Enhancement of the human HS response may eventually be a clinical goal in dealing with the aging population which may be more susceptible to environmental stress. Several investigators have now shown an age-dependent defect in the regulation of the HS response at the transcriptional level (Fargnoli et al., 1990). This defect has been observed in human peripheral blood lymphocytes and in... 

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... 

The function of the ALD protein is not fully understood, and knockout mice lacking it do not exhibit the severe CNS neurological deficits commonly associated with the human disease despite a similar accumulation of VLCFAs [26], Furthermore, the clinical variability in human patients cannot be accounted for by the severity of the biochemical abnormality or the nature of the gene defect. These observations, plus other data from mice with defects in VLCFA metabolism, raise the issue of whether the accumulation of VLCFAs in myelin is crucial to the pathological mechanisms or is an epiphenomenon. Unlike most other lipid-storage diseases, active ALD brain lesions are characterized by perivascular accumulation of lymphocytes. For this reason, it has been hypothesized that the severity of CNS pathology may relate to an autoimmune reaction that varies from patient to patient and... 

Yu, H.-S. et al., Defective IL-2 receptor expression in lymphocytes of patients with arsenic-induced Bowen s disease, Arch. Dermatol. Res., 290, 681, 1998. 

Bertotto, A., et al. Activation of cord T lymphocytes. II. Cellular and molecular analysis of the defective response induced by anti-CD3 monoclonal antibody, Cell. Immunol., 127, 247, 1990. 

Circulating neutrophils of patients with CHS contain giant azurophilic and specific granules that form during haematopoiesis, and stem cells with these abnormalities are seen in the marrow. Chemotaxis, degranulation and bactericidal activity of circulating neutrophils are all impaired (often delayed), and these defects, coupled with the neutropenia that may occur, result in increased susceptibility to infections. Lymphocyte and NK cell functions are also defective. 

Infection is the most common cause of morbidity and mortality in MDS patients, accounting for 40-60% of deaths in various studies. The common infections are those normally associated with neutropenias, such as Gramnegative septicaemia and bacterial bronchopneumonias. Indeed, most MDS patients are neutropenic at some stage in their disease. Even those who do not have a neutropenia may have a defect in their neutrophil function. Many patients have clearly-defined defects in T- and B-lymphocyte functions, and variable defects in monocyte numbers or function have been described. Disorders of neutrophil function are common. Many reports indicate that phagocytosis, chemotaxis, respiratory-burst activity and degranulation are defective in some MDS patients, and hypogranulation is often observed. 

In patients infected with HIV, many nonspecific and certain specific cellular immune functions can be shown to be altered or decreased, and a number of seemingly healthy individuals may exhibit marked immunological abnormalities without evidence of clinical illness. As the individual begins to exhibit clinical symptoms associated with AIDS, the abnormalities in the immune system become more extreme. A factor that complicates the study of HIV-induced immunosuppression is that many of the infections patients develop may themselves induce marked changes in the immune system. For this reason, it has been difficult to dissociate the fundamental changes associated with prolonged HIV infection from epiphenomena caused by other infections. One basic defect in the immune system of HIV-infected patients has, however, been elucidated. This is the loss of function and ultimate destruction of a proportion of T lymphocytes. 

Recently, it has been possible to grow cells of the human immune system in special mice. These mice carry a genetic defect called severe combined immunodeficiency (SCID), which leaves them with crippled immune systems, much like those in AIDS patients. Because SCID mice lack functional cellular immunity, it is possible to implant them with human cells without tissue rejection taking place. Researchers have recently developed techniques to implant human fetal tissues containing stem cells for the blood into SCID mice. It is then possible to reconstitute these mice with functional human immune system cells, including T lymphocytes and B lymphocytes. They have also found that if these SCID mice are infected by HIV, the virus will establish infection in the human tissue and destroy the T helper lymphocytes, just as it does in humans. Thus, it may be possible to study some of the mechanisms by which HIV attacks the immune system in these mice. In addition, they may be very useful for testing potential antiviral drugs. 

Gaudy AA, Reddy ST, Chatila T, Atkinson JP, Verbsky JW CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Chn Immunol 2007 119 482-487. 

As mentioned above, a subgroup of patients with atopic dermatitis has a filaggrin loss-of-function mutation Recently, it was shown that filaggrin expression is reduced in atopic dermatitis even in the absence of any mutation [29]. Keratinocytes differentiated in the presence of IL-4 and IL-13 exhibited significantly reduced filaggrin gene expression and neutralization of IL-4 and IL-13 improves skin barrier integrity [30]. This indicates that Th-2 lymphocytes directly contribute to the skin barrier defect in atopic dermatitis. 

Hawrylowicz C, Richards D, Loke TK, Corrigan C, Lee T A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroid-resistant asthmatic patients. J Allergy Chn Immunol 2002 109 369-370. 

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