Medical Hypotheses 16: 365-369, 1985

A I4DLEXXL.Q BYPOIHESIS COKEFWINGTWEPA~ ISOFMYASTHENIAGRAVIS

Iris Fletcher Norstrand. Brooklyn VA Wdical Center, 800 Poly Place Brooklyn, New York, 11209

Thepurine enzym, ademsine de aminase, is essential for the maturation of lyrqhocytes, cell growth and normlimrcune function. Since adeno-

z deaminase has the highest activity in the thymus and in T lyqho- s, it is hypothesized that a defective or altered enzyme may be a

cause of myasthenia gravis, a lmhoid dyscrasia. It is proposed that the alteration is on the non-catalytic portion of adenosine deaminase concernedwith the nomlimmme functionof Tlmhocytes. Lymphocytes, particularly suppressor Tlyqhocytes containing a defective adenosine deaminase will function improperly. They will lose their nom1 inmne regulatory function, allowing imnunoglobulin-producing Blmhocytesto produce autoantibodies against the nicotinic acetylcholine receptor, with resultant induction and perpetuation of the autoitmnme state. In anatteq&tocoqensate for thedefect, theremybehypertmphyof the thyms and lynphoid system, with overproduction of a defective adeno- sine deaminase. Since many of the functions of thymxin, the alleged active principle in thyms are identical to those of adenosine deaminase, it is postulated that thymsin my be a subunit of adenosine deaminase.

lXlXODUCTION

The evidence is now overwhelming that myasthenia gravis is an autoinamne diseaseintiich the endpoint is an attack on the nicotinic acetyl- choline receptor by autoantibodies, resulting in iqairedneurcmuscular tmnsnission (1). Eighty-five to 90% of patients with myasthenia (Travis have serumacetylcholine receptor antibody. Theirmuscles have a decreased nur&er of acetylcholine receptors, with autoantibody bound to residual receptors (2). Little is krmm, homver, about the details of acetylcholine receptor antibody production, including how and where the immne reaction to acetylcholine receptor takes place.

A) _* Role of thyms

Although the primary pathogenic site of myasthenia gravis is not known, my feel that the thymsmayplay an important part or evenbe the

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source of the disease. The human thymus consists of smll cells (lynph- ocytes) and large cells (epithelial cells) in a ratio of 1O:l. In my- asthenia gravis, the primary defect is believed to be limited to the epithelial or large cell population (3). Present studies support the concept of an important role of the thymus in the develolmentandmin- tenanceof the immne system. It is ill-known that the thyrms is responsible for the development of -tent cells and the T-cell lineage, as well as the regulation of imnunoglobulin synthesis by T cells. Moreover, thymic epithelial cells and thymcytes in the normal and myasthenia gravis thymus contain acetylcholine receptor (3). It has been theorized that this thymic acetylcholine receptor, scmshowaltered, may be the putative thymic neo-antigen (4). There is also evidence that the thymus, in both normal and myasthenia gravis patients, is a site of antibody production (5). Studies have shown that B cells form anti- acetylcholine receptor antibody, and that T cells, which help these B- cells, are increased in the thymus and peripheral blood of myasthenia gravis patients. The sensitive suppressor T cells, which regulate anti- acetylcholine receptor antibody formation are, on the other hand, decreased in myasthenia gravis patients. The occurrence of thymichyper- plasia and thymmas in myasthenia gravis is further evidence iqlicating the thymus in the immnobiology of this disease (6,7). It is not certain, hover, what triggers the thyms in myasthenia gravis to beccm hyperplastic or thymmatous, or what are the molecular events by which the gland exerts its pathogenic imnunoregulatory action. It is wzll- known that thymctomy often benefits patients (8).

The term "thymsin" was first applied in 1961 by Goldstein and White (9) to the active principle of the thymus gland, which was partially puri- fied from calf thymus homogenates (10,ll). Several distinct and active polypeptides have been extracted from thymic tissue (10). These are potent immnopotentiating preparations that can increase cell growth, influence antibody reqxmse,&affect maturation and differentiation of T lymphocytes (12). By rreans of an inmunofluorescence technique, it has been found that the origin of the thymic hormone alpha-l-thyrmsin is the thymic epithelial cells, which appear to be increased in hyperplastic or thyrmmtous thymuses of myasthenia gravis patients (12). It is believed that thyrmsin irrbalances my be involved in the etiology of autoimnune diseases (13).

3) - Role of adenosine deaminase

Adenosine deaminase, an inducible enzyrms found in the cytosol, and in- volved in the purine salvage pathway, catalyzes the irreversible deamina- tion of adenosine and deoxy-ademsine to imsine and deoxyinosir~ respect- ively, and mnia. TW forms of human adenosine deaminase (oue with a molecular weight of 35,000-45,000, and the other, with a molecular weight of 200,000-300,000) have been distinguished (14). The low molecular weight form has been purified to hcmgeneity frcnn erythrocytes (14,15), thyms tissue (16), and kidney (17). Adenosine deaminase has the high- est activity in the thyms and in lyrrphoid tissues, particularly T lmh- ocytes , is high in T lynphoblasts, but very low in B lyn-phoblasts. Hman skin also has a high level of the enzyme (18). Adenosine deaminase hasbeendetected inmumhistochemically in human thyms (19), where it is

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found pred cminantly in cortical thymocytes.

Adenosinedeamina se is essential for the maturation of lyrrphocytes, cell growthandnorml immme function, in addition to its role in the regu- lation of extracellular levels of brain adenosine. Occurrence of a large amour&of the enzymaincorticalthymocytes andleukticlynpho- blasts of the thymic phenotype *lies that these cells my be espec- ially dependemt on adenosine deaminase for function and survival.

Frm a clinical standpoint, a deficiency or absence of adenosine deami- nase in white and red cells results in profound depletion of lyrrphoid tissues and severe ccxtbined immmodeficiency (20). Adenosine deaminase is also low in the lymphocytes of patients with chronic lyrqhatic leu- kemia (21,22). It is markedly increased in blast cells of patients with acute myelogenous leukemia, acute lynphocytic leukemia, patients with transplanted kidneys, scma patients with Waldenstrm's macroglobulinemia, and cancer patients with liver metastases.

I5FmHFs1s

Despite the high activity of adenosiue de aminaseinthethymsandinT lyrrp?hocytes, which are involved in imtnme reactions, scientists thus far have not considered the possible importance of this enzyne in the pathogenesis of myasthenia gravis, a lmhoid dyscrasia. It is there- fore hypothesized that a defective or altered adenosine dearCnase may be a cause of myasthenia gravis. It is proposed that the alteration is not on the catalytic site of the enzyme so that the deamination of adenosine is not affected. Rather, the defect is on the non-catalytic portion of adenosine deaminase concernedwith the normal immne function of T lmhocytes. Lyqhocytes, particularly suppressor Tlynphocytes contain- ing adefective adenosine de minase will function improperly. They will lose their normalimrnme regulatory function, allowing immnoglobulin- producing B lyqhoqtes to produce autoantibodies against the nicotinic acetylcholiue receptor, with resultant induction and perpetuation of the autoimnune state. In an attempt to corrpensate for the defect, there may be hypertrophy of the thymx and iymphoid system, with overproduction of a defective adenosine deaminase. Mxeover, because of the above abnor- mlities, the concentration of adenosine may be affected. Since adem- sine can markedly increase or decrease the concentration of cyclic AMP (23) via the enzyme adenylate cyclase through admosine receptors, the concentration of acetylcholine nay be indirectly affected, with adverse effects on neurcmuscular transnission. At the opposite end of the spectrum, a deficiency of adenosine deaminase in white and red cells results in profound depletion of lmhoid tissues and severe cca-rbined immncdeficiency (20).

It is quite possible that adenosine deaminase itself my be the acetyl- choline receptor. An altered adenosire deminase, being a high rrole- cu1a.r weight foreign protein my actually be the sought after putative thymic neo-antigen, stimulating the formation of antibodies to itself.

And lastly, th~ymxin, a polypeptide, and presumably the active principle in thymus, may actually be a subunit of adenosine deaminase. Many of

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the alleged functions of thyn-osin, such as its potent inmxop&entiating effects consisting of mturation and differentiation of T lymphocytes, influence on antibody response and cell grcwth, are identical to those of adenosine deaminase. It is of interest that Chechik, Schrader and Daddona (16) demonstrated that the leukemia-associated antigen found inthyrrolsisrroneotherthanadenosinedeaminase. Very possibly, the thymic factor involving T-lyrrq?hocyte maturation (231, which has been iqlicated as playing a role in childhood myasthenia, may likewise be adenosine deaminase.

The above hypothesis awaits experinental verification.

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