The Immune System

The Immune System

To accomplish its task, the immune system has developed two mechanisms: one is the natural (innate) immune system, composed of various white blood cells (granulocytes, macrophages and natural killer [NK] cells) that non-specifically ingest microbes, tumor cells and virus-infected cells. Second is the acquired (specific)immune system, which is characterized by learning, adaptability and memory. Its major components are two subsets of lymphocytes: T-cells that are primarily thymus-derived and B-cells that are bone marrow-derived. The T-cell dependent part of the immune system is the most susceptible to aging.

T-helper cells regulate immune reactions involving antibody production and inflammation. They are the second line of defense after the non-specific defense of macrophages and natural killer, cells. There are two kinds of T-helper cells. Depending on the cytokines available (cytokines are hormone-like proteins which facilitate communication within the immune system and regulate the intensity and duration of immune responses), T-helper lymphocytes can develop into either Th1 or Th2 cells. The cytokines interferon gamma and interleuken 12 enhance the development of Th1 bias, and interleuken 4 and interleuken 10 enhance the development of Th2 bias. In general, Th1 cells promote cellular immunity, the anti-cancer and anti-viral mode of the immune system, whereas Th2 cells promote humoral immunity, more related to allergic reactions and asthma.

TNF-a induced apoptosis(*) (programmed cell death/cell suicide) is regulated by the CD 95 receptor/ligand system also known as Fas/FasL. Recent studies have provided evidence that the Fas/FasL system is involved in the molecular mechanism of T-cell depletion in AIDS (Westendorp MO et al., 1995), cancer (Hahne M et al., 1996) and aging (Aggarwal S et al., 1999).

The Fas ligand (FasL) is a transmembrane protein that induces apoptosis in susceptible cells by interacting with its receptor, Fas. Fas and FasL are involved in the regulation of the immune response and deletion of auto reactive (self reactive) lymphocytes (Brunner T et al., 1995) and participate in T-cell mediated cytotoxicity (Lowin B et al., 1994). Many tumor cells express FasL on their surface and induce the apoptosis of immune effector cells, which express the Fas receptor, in the tumor microenvironment. Extensive recent research suggests that the Fas/FasL system can play a stimulating role in the growth of some tumors (Lee J et al., 1999).

Previous studies have provided evidence that the Fas/Fas ligand system is involved in the molecular mechanism of T-cell depletion in HIV-1 infection and AIDS (Westendorp MO et al., 1995). An increased susceptibility to FAS-mediated apoptosis is caused by the chronic expression of Fas/FasL and the unregulated activation of the receptor for TNF-a.

In an interesting pilot study, eleven HIV-infected subjects, who refused any anti-retroviral drug treatment in spite of declining CD4 counts (a subgroup of T-cells), were treated with daily infusions of L-carnitine for four months. This therapy resulted in a significant increase in CD4 counts (an independent predictor of the risk of developing AIDS), and a reduced frequency of T-cell apoptosis. The same individuals who showed an increase in CD4 cell counts reported an increased sense of well-being and less fatigue. The authors stated that L-carnitine interfered with the Fas-induced apoptosis signal, a major mechanism for the loss of CD4 and CD8 cells (T-lymphocytes) during the progression of HIV infection towards AIDS (Moretti S et al., 1998).

In human aging as well as in HIV infection, increased Fas-mediated apoptosis is associated with increased proportions of Fas/FasL positive cells. Recently it was shown that T-cells from aged humans have an increased susceptibility to Fas-mediated apoptosis as compared with young subjects. Lymphocytes in aged humans are more susceptible to TNF-induced apoptosis, which is associated with increased activation of the apoptotic pathway and decreased expression of molecules involved in antiapoptotic pathway of TNF-a induced cell death. The authors concluded that increased serum levels of TNF-a and increased susceptibility of T-cells to TNF-induced apoptosis may play a role in the pathogenesis of lymphopenia (a reduction in the number of lymphocytes in blood circulation) and lymphocyte dysfunction associated with human aging (Aggarwal S et al., 1999).

(*) Apoptosis is a programmed, highly organized form of cell death, when cells commit suicide by chopping themselves into membrane-wrapped pieces. A certain amount of apoptosis is critical to health. When the process is malfunctioning, too little programmed cell death causes cancer and autoimmune diseases, while too much causes neurodegenerative diseases such as Alzheimer's disease.

Life Extension Foundation.

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