Lymphocytes function, defects

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. 

Attempts to establish a connection between iron deficiency, impairment of neutrophil and lymphocyte function, and increased rale of infections have not been conclusive to date, One complicating issue in making the connection between iron deficiency and resultant infections is that sonxe infections can induce iron deficiency One example Is the hookworm infection, described later in this seclion-Among the most severely iron-deficient people in the wcirld arc children in Africa in areas where malaria is prm alcnt. The children die of malaria rather than of physiological defects resulting from the iron deficiency. 

Irani, A.A., Craig, S.S., DeBlois, G., Elson, C.O., Schechter, N.M. and Schwartz, L.B. (1987a). Deficiency of the tryptase-positive, chymase-negative mast cell type in gastrointestinal mucosa to patients with defective T lymphocyte function. J. Immunol. 138, 4381-4386. 

Congenital defects and chemical inhibitors of these enzymes result in the accumulation of purine nucleosides and nucleotides which have been directly linked to impaired lymphocyte function and immunodeficiency syndromes (4,5). Since the uremic state is complicated by an increased susceptability to infection largely the result of acquired l3nnphocyte abnormalities, we have studied the ability of uremic erythrocytes (RBC) to metabolize vitro radiolabelled adenosine and deoxyadenosine utilizying a combind UV - radioactive high performance liquid chromatographic technique (HPLC) (1,2,3). 

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. 

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... 

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. 

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. 

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. 

In this overview we have highlighted the normal biochemical functions of platelets, neutrophils, and lymphocytes. We have attempted to relate defects in these cells to derangement in function. With the explosion of knowledge in the chemistry, immunology, and molecular biology of these cells, it is to be hoped that in the near future we will come to a fuller understanding of the basis of hematological disease. 

Physiologically, these plasma changes are included here since they reflect impaired numbers or function of B-lymphocytes. Two broad categories are recognizable. First, such immunodeficiency states may exist on congenital basis and often do so with concurrent defects in the T cells (Fig. 1). Alternatively, severe reductions in immunoglobulin levels often develop in the course of chronic lymphocytic leukaemia and myeloma. Not dissimilar impairment of immune competence is found with nephrotic syndrome, protein-losing enteropathy or even malnutrition, and in these instances is equally profound. 

While confirming the general normality of the mutant mice and problems with lymphocyte homeostasis, these studies focused on identifying defects in peripheral leukocytes. The Lsc- - mice had a twofold increase in circulating neutrophils and lymphocytes but normal platelet counts and red blood cells. In functional studies, the Lsc-/ neutrophils showed a reduced ability to stimulate formation of Rho-GTP and abnormal pseudopod development in response to fMLP. An increased motility and lower adherence of the neutrophils when stimulated with fMLP (Francis et ah, 2006) are similar to the behavior of B cells from Lsc / mice when stimulated with serum (Girkontaite et ah, 2001). While these studies imply a role for a G12/i3 Lsc-RhoA pathway in the phenotypes of these cells, the molecular details are not yet known. 

---