Autoimmunity and the Concept of Self

Defects of the immune system may involve the B-cell compartment, which leads to poor antibody production, or the T-cell compartment, which causes defects in cellular immunity, or both T- and B-cell compartments.

The prevalence of autoimmune diseases in women may be the consequence of a bidirectional signaling network between hormones and the immune system that regulates female reproductive life. Two prototypical autoimmune diseases, rheumatoid arthritis and systemic lupus erythematosus, arise from 2 different immune responses that generate mutually exclusive signals in response to different inflammatory triggers.

Certain estrogens may ameliorate the rheumatoid-arthritis-like TH1 response while exacerbating the lupus-like TH2 response. Studies of sex hormone metabolism in lupus patients reveal increased 16-hydroxylation of estrone in some patients and decreased levels of androgens as a result of increased oxidation at C17. These occurrences result in low serum levels of dehydroepiandrosterone (DHEA). Both the increase of 16-hydroxylation of estrone and the depletion of DHEA have immune effects that would tend to exacerbate a lupus-like TH2 response. This theoretical framework provides a rationale for ongoing initial clinical trials of exogenous hormones in autoimmune diseases.

¥ Viruses and how they work

Viruses are small, obligate intracellular parasites which cause infection by invading cells of the body and multiplying within them. Within their life cycle they have a relatively short extracellular period, prior to infecting the cells, and a longer intracellular period during which they undergo replication.

The immune system has mechanisms which can attack the virus in both these phases of its life cycle, and which involve both non-specific and specific effector mechanisms.

Non-Specific Mechanisms Interferons: Viral infection of cells directly stimulates the production of interferons (*note that the "type 1" interferons which are produced non-specifically by many cell types in response to viral infection are quite distinct from the T cell cytokine gamma interferon which is produced by CD4+ and CD8+ T cells in response to antigenic stimulation).

Type I interferons lead to the induction of an "antiviral state" in the cells, which is characterised by inhibition of both viral replication and cell proliferation, and also enhancement of the ability of natural killer cells to lyse virally infected cells .

Natural Killer Cells: Natural killer (NK) cells are a subset of lymphocytes found in the blood and tissues, which lack antigen specific surface receptors (TcR or immunoglobulin receptors). Phenotypically, NK cells do not express the characteristic cell surface markers that define T cells and B cells, and so NK cells represent a distinct lineage of lymphocytes. NK cells possess the ability to recognise and lyse virally infected cells and certain tumour cells. Whilst not showing antigen specificity, they clearly exhibit some degree of selectivity in targeting "abnormal" cells for lysis.

The nature of the receptor (or receptors) that confer this selectivity of target recognition has not been clearly defined, but it has been shown recently that the expression of "self" MHC molecules inhibits NK lysis of target cells. The main advantage that NK cells have over antigen-specific lymphocytes in antiviral immunity is that there is no "lag" phase of clonal expansion for NK cells to be active as effectors, as there is with antigen-specific T and B lymphocytes.

Thus NK cells may be effective early in the course of viral infection, and may limit the spread of infection during this early stage, while antigen-specific lymphocytes are being recruited and clonally expanded. Specific Mechanisms Both humoral and cell mediated arms of the immune response play a role as specific effector mechanisms in antiviral immunity.

Antibody: Specific antibodies are important in and may protect against viral infections. Antibody production is only described here in relation to its role in antiviral immunity. The most effective type of antiviral antibody is "neutralizing" antibody - this is antibody which binds to the virus, usually to the viral envelope or capsid proteins, and which blocks the virus from binding and gaining entry to the host cell.

Virus specific antibodies may also act as opsonins in enhancing phagocytosis of virus particles - this effect may be further enhanced by complement activation by antibody-coated virus particles. In addition, in the case of some viral infections, viral proteins are expressed on the surface of the infected cell. These may act as targets for virus-specific antibodies, and may lead to complement-mediated lysis of the infected cell, or may direct a subset of natural killer cells to lyse the infected cell through a process known as antibody-directed cellular cytotoxicity (ADCC).

At mucosal surfaces (such as the respiratory and gastrointestinal tracts), virus infection may induce the production of specific antibodies of the IgA isotype, which may be protective against infection at these surfaces. (This is the basis of immunisation with the current oral polio vaccine). Not all antibodies to viruses are protective, however, and in certain cases antibody to the virus may facilitate its entry into a cell through Fc receptor-mediated uptake of the antibody coated particle. Such antibodies are called enhancing antibodies. During the course of a viral infection, antibody is most effective at an early stage, before the virus has gained entry to its target cell. In this respect, antibody is relatively ineffective in primary viral infections, due mainly to the lag phase in antibody production.

Preformed antibody, particularly neutralising antibody, however, is an effective form of protective immunity against viral infections, as witnessed by the success of many viral vaccines, which work by stimulating virus-neutralising antibody responses.

Cytotoxic T Cells: The principal effector cells which are involved in clearing established viral infections are the virus specific CD8+ cytotoxic T lymphocytes (CTL). These cells recognise (viral) antigens which have been synthesised within cell's nucleus or cytosol, and which have been degraded. They are presented at the cell's surface as short peptides associated with self class I MHC molecules. The recognition of antigen by CD8+ T cells is, therefore, distinct from that of CD4+ T cells in several respects.

It requires synthesis of the target antigen within the cell (and is therefore restricted largely to virally infected or tumour cells); it is "restricted" by class I MHC molecules (as opposed to MHC class II restriction for CD4+ T cells); MHC class I molecules are expressed on almost all somatic cells, so virtually any cell, on infection with virus, can act as a "target" cell for antigen specific CTL (contrasts with the limited tissue distribution of class II MHC); recognition of an antigen presenting cell (APC) by an antigen-specific CTL usually results in the destruction of the APC.

The importance of CTL in the clearance of virus infection has been demonstrated in a wide variety of viral infections in both laboratory animals and in man. In addition, adoptive transfer of virus-specific CTL in mice has been shown to protect the recipient against infections with the virus. As with virus-specific antibody responses, however, not all CTL responses to virus are beneficial to the host, and in some cases the tissue destruction caused by the virus-specific CTL is greater than the damage done by the virus itself; and example of this would be the fulminant hepatitis associated in a small proportion of cases with infection with hepatitis B virus, in which the liver damage is caused by virus-specific CTL rather than directly by the virus.

¥ Immune deficiency Conditions

Human leukocyte antigens (HLAs) are an inherent system of alloantigens, which are the products of genes of the major histocompatibility complex (MHC). These genes span a region of approximately 4 centimorgans on the short arm of human chromosome 6 at band p 21.3 and encode the HLA class I and class II antigens, which play a central role in cell-to-cell interaction in the immune system.

These antigens interact with the antigen-specific cell surface receptors of T lymphocytes (TCR) thus causing activation of the lymphocytes and the resulting immune response. Class I antigens restrict cytotoxic T-cell (CD8+) function thus killing viral infected targets, while class II antigens are involved in presentation of exogenous antigens to T-helper cells (CD4+) by antigen presenting cells (APC).

The APC processes the antigens, and the immunogenic peptide is then presented at the cell surface along with the MHC molecule for recognition by the TCR. Since the MHC molecules play a central role in regulating the immune response, they may have an important role in controlling resistance and susceptibility to diseases. The general perception that primary immunodeficiency diseases are found only in infancy or early childhood is incorrect.

The majority of individuals diagnosed with congenital immune defects are over age 21. IgA deficiency, by far the most common of the primary immunodeficiencies, occurs in 1 of 300 to 1 of 1000 adults. Another impression is that congenital immune defects are rare. However, even excluding IgA deficiency, taken together, the primary immunodeficiency diseases are as common as leukemia andlymphoma.Because the most frequent manifestations of these diseases include unusual susceptibility to infections, weight loss, and/or failure to thrive, the diagnosis of HIV is often considered before any other immunodeficiency disease; this can lead to a delay in diagnosis and treatment, and added stress for the patient and family.In fact, a number of conditions and disease states are common to both primary immunodeficiency and HIV disease

¥ HIV

Infection of cells by HIV is a multistage process. A glycoprotein (gp120) on the surface of the virus binds to CD4 receptors on t-helper cells ,which then internalize the virion. After entry into the cell, the virion RNA is converted by reverse transcriptase( also contained in the virion) to a double stranded DNA provirus that then becomes integrated into the host genome.

Using the reverse transcriptase , the virus further reproduces in these cells and increases its number resulting in viremia. Reverse transcription is essential for the further replication of the virus and subsequent productions of virions and/or cytopathology. Since the virus can be transmitted in breast milk and semen, even cells not expressing CD4 may also be infectable. During infection HIV is not attacked by the normal scavenging macrophages eventually causing the destruction of the t-helper cells .

All individuals infected by HIV show a reversal of the normal ratio of t-helper to t-suppresser cells . The incubation period of the virus can run from 2 to 6 months. The resulting infection over a 5-8 year interval causes an irreversible depression of cell-mediated immunity leading to death from opportunistic infections, e.g., fungi, TB or rare malignancies.

The clear-cut heterosexual transmission of AIDS by prostitutes and blood transfusion has increased . AIDS is now the number one cause of death of young American women. HIV antibody screening tests have been developed to prevent AIDS spread through the nations of the world and their blood supply . Current testing only reveals the tip of the iceberg. The Effects of HIV Infection on the Immune Response:

Infection with the human immunodeficiency virus (HIV) represents something of an immmunological paradox, in that HIV induces a strong antiviral immune response, whilst simultaneously and progressively disrupting the ability of the immune system to respond to new infections and antigens, ultimately leading to a severe immune deficiency of the cell mediated immune system: Infection with HIV is associated in the majority of cases with the production of virus specific antibody, some of which can be shown to neutralise the virus in vitro.

In addition, there is a strong virus specific CTL response to the virus in the majority of patients (which is associated with an initial and dramatic fall in virus titre). This CTL response does not appear able to clear the virus, however, and persistent infection follows. There is a progressive decline in the number of CD4+ T cells over time, which often accelerates as the patient progresses towards AIDS, at which the CTL response falls away and viral titres rise.

HIV uses the CD4 surface marker as its receptor for gaining entry to cells. HIV therefore predominantly infects CD4+ cells, and leads to a disruption of the function of these cells, and a progressive decline in their numbers. As described previously, CD4+ T cells play a central role in regulating the immune response, and so HIV infection leads to a disregulation of many aspects of the immune response, including defective antibody and T cell responses to new antigens, and decreased NK responses. These effects can be detected even when numbers of CD4+ T cells are relatively normal. As CD4+ T cell numbers decline, however, the defects become more marked, leading to a state of immunodeficiency which leaves the host susceptible to infection with a variety of common or opportunistic infections and to certain types of tumours.

How does HIV manage to persist in the face of such a strong antiviral immune response ? Like many persistent viruses, HIV has a number of strategies for evading the host's immune response. One of the most important of these is the ability to undergo "antigenic variation" - the ability to mutate key epitopes which are recognised by the immune response. This has been shown for both antibody and T cell epitopes in HIV infection. (The antigenic "drift" and "shift" in the coat proteins of influenza virus is another example of antigenic variation.)

In addition, HIV is capable of existing within an infected cell as a provirus - a state known as viral latency, in which the virus exists within the cell but does not replicate, so that very few viral antigens are expressed in the cell. The fact that HIV infects cells of the immune system also plays a role - in attacking the virus, the host progressively damages its own immune system, contributing to the immune dysfunction and ultimately to the survival of the virus. It has also been proposed that HIV infection leads to a disregulation of the balance between Th1 and Th2 cells in the body generally. This may contribute to the susceptibility of the HIV-infected individual to infections with intracellular organisms such as Mycobacteria, as was discussed in the previous session.

¥ HTLV 1 and 11, the Other Immune Deficiency Diseases

¥ AIDS and the Primary Immune Deficiency Diseases

Primary immunodeficiency diseases are the result of naturally occurring defects of the genes that govern immune functions. More than 70 immune deficiency diseases have been identified, many in the past 40 years. Prior to that time, a few well-characterized defects had been described, including mucocutaneous candidiasis, first reported in 1924, ataxia-telangiectasia in 1926, and Wiskott-Aldrich syndrome in 1937. Since 1950, a number of additional immune defects have been reported, including Bruton's X-linked agammaglobulinemia (1952), hypogammaglobulinemia in an adult (1954), severe combined immunodeficiency (SCID) (1958), and DiGeorge syndrome (1965).

The HIV virus which caises Acquired Immune Deficiency Syndrome, AIDS, has the ability to incorporate itself into the DNA of human lymphocytes. As a retrovirus it can further multiply in these cells and increase its number resulting in the destruction of the t-helper cell subtype of lymphocytes in the resulting viremia. At the same time it apparently is not attacked by the normal scavenging white blood cells such as macrophages and T cells. The retrovirus is sexually transmitted by bodily fluids including breast milk and semen. The incubation period of the virus can be up to 6 months.

The resulting infection over a five year interval causes an irreversible depression of cell-mediated immunity leading to death from opportunistic infection or rare malignancy. The clearcut heterosexual transmission of AIDS by prostitutes and blood transfusion has increased . Many HIV antibody screening tests have been developed to prevent AIDS spread through the nations blood supply . All individuals infected by HIV show a reversal of the normal ratio of t-helper to t-suppressor cells . Once the CD4 helper cell level falls into the 200 to 500 c/ccm range, antiviral therapy has been started and AIDS is present. Lentinan and antiretrovirals, AZT, DDI, DDC, etc. together may have a synergistic effect to increase survival.

¥ Immune excess diseases

Rheumatoid Arthritis, Asthma, Renal Diseases, Collagen Vascular diseases eg. Lupus, Scleroderma, Reflex Sympathetic Dystrophy Multiple Sclerosis Lou Gerig's Disease or Amyotrophic Lateral Sclerosis

5. How have mushrooms been used as drugs

¥ Antineoplastic medications (AntiCancer Drugs)

In the Rhesus monkey, an intravenous dose of 0.5 mg/kg given as an infusion for 26 weeks was found to have significant antitumor activity. Higher doses (up to 30 mg/kg per day x 26 weeks) were associated with skin rash, development of foam cells in the liver and presence of a palpable spleen and lymph nodes.

In 235 cancer patients, Lentinan used in combination with standard chemotherapy (mitomycin C and 5-FU or tegafur) to define its antitumor activity and to document its side effects. Results were most positive and beneficical. Life expectancy was increased significantly with clinical improvement in tumor response to the treatment regimen. An increase in peripheral blood lymphocytes was also observed .

Recently Lentinan , in combination with Interleukin-2 has been found to stimulate lymphokine activated killer cells. Lentinan has already been shown effective in gastric carcinomas and a preclinical screen by NCI proved a reduction in lung metastases and prolonged survival time in mice. In 145 patients, Lentinan was tested in inoperable gastric cancer in combination with 5FU. One to three ear survival rates were observed from 6.5 to 10.4% by comparison, survival rates on (5FU) alone were 2.9%, 2.9%, and 0%. Side effects were mild, occurring in 6.8% of the patients. Reported side effects included skin eruption and redness, chest pressure, nausea and vomiting, headache, hot flashes, sweating, fever and bone marrow suppression.

6. Fungal extract used as immune suppressant-

¥ Cyclosporin

Cyclosporin or Sanimmun Neoral is used in cases where there may be immune system problems, for example to prevent transplant rejection. Cyclosporin or Sanimmun Neoral is also used in auto immune conditions, for example psoriasis, rheumatoid arthritis. Neoral is a microemulsion formulation with more complete and consistent absorption. Cyclosporin or Sanimmun Neoral interferes with the body's immune response basically preventing the body's immune response. Cyclosporin or Sanimmun Neoral can cause kidney problems, increased blood pressure, and tremors. These may be of a serious nature and any one taking Cyclosporin or Sanimmun Neoral is closely followed.

¥ Transplantation successes and Cyclosporin

Cyclosporin is a cyclic peptide that has a selective action on the generation of helper T cells, which do not become functional while the drug is present; produced by fungi and used as an immunosuppressive agent, particularly in the suppression of graft rejection after transplantation and likely to prove valuable in the treatment of autoimmune diseases such as those involving the skin , eyes and pancreas.Cyclosporin is a drug typically used in organ transplants to prevent the body rejecting the organ by suppressing the immune system. It is also used topically in the treatment of some severe skin conditions as atopic dermatitis and severe psoriasis. Cyclosporin has been shown to be very effective orally and intramuscularly.

¥ A Pilot Study of Cyclosporin-A in Modulating Immune System Activation in HIV-1 Disease

New Direction in HIV-1 Research Hits Bay Area A new approach to treating HIV disease is being implemented by researchers in the bay area. Their approach is novel in that the therapy focuses directly on the immune system rather than on HIV which is the target of conventional therapy using antiretroviral drugs.

This approach is also different from other therapies in that it attempts to control HIV by suppressing the immune system and will test some novel ideas about exactly how HIV causes disease. Using the drug "Cyclosporin A" they hope to slow down the immune activation which is associated with the progression of HIV disease.

This approach may be particularly useful in patients who do not benefit from protease inhibitors. Despite recent progress in the treatment of HIV infection, the mechanism by which HIV damages the immune system is still not fully understood. This would not be an issue if HIV could be eradicated from the body before drug resistance develops. Elimination of this virus is a worthy goal which should result in better health and longer survival regardless of the disease mechanism, but it has not yet been demonstrated. After all, if the virus causes immumodeficiency and the virus is gone, the destruction of the immune system should slow down, stop , or even reverse. However it is already clear that many HIV infected individuals (for a variety of reasons) do not get, or cannot sustain, a large reduction of viral load, even with the best known treatments. For these individuals, a different approach may lead to the treatment of the disease mechanism even when the viral load can't be reduced or eliminated.

The most widely held concept of the disease mechanism is that the virus kills more CD4 cells than the body can replace. An alternative theory is that the body is actually quite capable of replacing CD4 cells but the very process which maintains the correct number of CD4 cells is "confused" or perhaps "overworked" by excessive immune activation, a well known consequence of HIV infection.

If the idea that HIV-1 causes AIDS by excess immune activation is true, the logical treatment would be to eliminate the ex cess immune activation, returning the immune system to more normal function. In the mid-1980's scientists had this very idea and were bold enough to try a drug called Cyclosporin-A (CsA), an immune suppressing drug used in patients receiving kidney transplants, to try to treat patients with AIDS. At the right dose, CsA prevents kidney graft rejection but does not cause severe immunodeficiency. The idea is that , in HIV infected individuals, CsA might eliminate the excess immune activation without interfering with normal immune defenses. Unfortunately this pioneering research received limited support and attention as research has focused on viral eradication.

Additionally, there was not much known about the immune system in HIV-1 infection and what was the best way to measure or predict immune restoration. But some of the patients, treated with CsA, did well clinically and had increased CD4 counts. Other HIV-1 infected patients who received CsA as part of their treatment for kidney transplants also did well, taking significantly longer to develop AIDS than patients who did not receive CsA.

7. Fungal immunomodulators- Lentinan and PSK

¥ Lentinan - Ajinomoto Lentinan , (MW 500,000 daltons), is a purified polysaccharide of a Beta glucan extracted from the edible mushroom Lentinus edodes. It appears to be very similar to the specific RNA type coding for the T helper cell. For many years, Lentinan has safely been used as an antitumor agent in Japan and has been demonstrated to have both immune potentiating activity by stimulating the T-cell mediated cytotoxic immune response and also positively effecting a non-specific macrophage mediated responses.

Daily use of a Lentinan containing powder, orally, produced increase in CD4 numbers in healthy humans without side effects. {According to clinical studies, Lentinan produces specific T-helper cell (CD4 cells) stimulation in healthy humans as well as animals. Lentinan has also been found to stimulate lymphokine activated killer activy in combination with Interleukin-2 . ÒThe drug has a host-mediated activity, and an effector mechanism that involves killer T cells, activated macrophages, natural killer cell, and antibody dependent macrophage mediated cytotoxicity (ADMC).} ( Ajinomoto insert).

¥ PSK (Krestin)-MRL PSK is a protein-bound polysaccharide prepared from cultured myelium of the Basidiomycete Coriolus versicolor. Effects of PSK on the immunologic responsiveness in both aged and tumor bearing animals were remarkably similar indicated a basic immune effect of restoration of depressed immunologic function. In humans with gastrocarcinoma in Japan, when PSK was administered orally for more than 2 weeks, increased CD4 cells were found in the regional lymph nodes at the time of surgery .

¥ Sizofilan (SPG)-Kaken Pharmaceuticals

8. Mycological Immune stimulants- Reishi and Cordyceps

¥ THE MEDICINAL USES OF REISHI

Reishi is a basidiomycete, a lamellaless mushroom belonging to the Polyporaceae. There are six varieties of reishi, and they grow almost exclusively on old plum trees. Because of its glossy appearance, it has been compared to a beautifully lacquered ornament. For at least two thousand years, reishi has been regarded in China as a medicine to promote longevity and a specific against incurable diseases, especially cancers. Reishi has also been accepted as a traditional medicine in Japan. According to Japanese natural health author Kosai Matsumoto II, in Traditional Herbs For Natural Healing: Japanese Plums (Ume) and Shelf Mushroom (reishi), the Chinese today believe reishi to be effective in coronary and circulatory conditions and liver conditions. Contemporary clinical tests have also found reishi effective against chronic bronchitis, - stomach ulcers, and high bloodpressure. The Chinese use reishi and other polypores in the treatment of various cancers.

¥ Cordyceps

9. How to order your own mycologic extracts Raw Material- purity Production and Packaging in England Quality Control- Ongoing clinical trials to confirm effectiveness

REFERENCES

1. US Council on Scientific Affairs. ( OCT. 1984) The Acquired Immunodeficiency Syndrome. JAMA 252:15 , 2037.

2. Redfield, R.R., (1985) Frequent transmission of HTLV-11 among spouses of patients with AIDS-related complex and AIDS. JAMA 253:11, 1571.

3. Miyakoshi,H.,Usuda, Y. et al. (1985) Antigens of HTLV-1 and/or 111 and their antibodies as clinical criteria for the efficacy of Lentinan administration. Int. J. of Immunopharmacology 7:3, 332.

4. Katzenstein, D. , Merrigan , T. (1992) The effect of AZT and DDI in AIDS. (ongoing).

5. Suzuki,M., Higuchi, S. , Taki, Y.,Miwa, K. ,Hamuro,J., (1990) Activity of Lentinan and Interleukin 2. Int. J. of Immunopharm.12(6) 613-623.

6. Kryger,A.H.,(1983) The Lentinan phenomenon . Unpublished -see: http://www.wellnessmd.com/articles.html

7. Dennert, P. et al. (1973) Antitumor polysaccharide Lentinan-a T cell adjuvant. J. of National Cancer Institute.51, 1727.

8. Valle, S.L., et al. (1985) Diversity of clinical spectrum of HTLV-111 infection. Lancet, Feb

9,1985. 9. Chihara, G. , Hamuro, J., Maeda, Y.Y., Arai, Y & Fukuoka, F. (1987) Function and purification of the polysaccharides with marked antitumor activity, especially lentinan, from Lentinus edodes (Berk.) Cancer Res., 30,2776-2781.

10. Taguchi, T., Furue,H.,Kimura, T.,Kondo, T., Hattori, T., Itoh, T,. and Osawa,N. (1985) End-point results of phase 111 study of lentinan. Japan. J. Cancer Chemother. 12:366

11. Chihara, G. (1981) Randomized controlled trial of Lentinan use in advanced human gastric malignancy. Gann 8:6.

12.Talmadge, J.E., (1986) Preclinical screen for biological response modifiers. Pers. Communication, NCI-Frederick Cancer Research Facility.

13. Hanaue,H., Tokuda,Y. , et al. (1989) Effects of oral lentinan on T-cell subets in peripheral venous blood.11(5): 614.

14. Rook, A.H. et al. IL-2 enhance the depressed natural killer cell and cytomegalovirus-specific cytotoxic activities of lymphocytes from patients with AIDS.(1983) J. Clin. Invest. 72,393.

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