Jack P. Antel

Neuropathy accompanying IgM? monoclonal gammopathy

SummaryA set of observations made on a patient with IgMλ monoclonal gammopathy and neuropathy implicate humoral immunity in the pathogenesis of the neuropathy.A sural nerve biopsy from the patient showed a characteristic increase in the width of the intraperiod lines. Deposits of μ-heavy chains and λ-light chains were found in myelin sheaths of the nerve biopsy. Immunohistochemically, it was demonstrated that μ-heavy chains and λ-light chains from the patients serum bound to myelin sheaths of normal peripheral nerves and to a lesser extent to myelin sheaths in the central nervous system (CNS). By immunoblots it was demonstrated that μ-heavy chains and λ-light chains from the patients serum bound to myelin associated glycoprotein but to no other antigens from the peripheral and central nervous systems. γ and α heavy chains and ϰ light chains from the patients serum were also shown to bind to myelin-associated glycoprotein but not as distinctly as the μ and λ chains. It is postulated that the monoclonal gammopathy may have arisen on the background of polyclonal autoimmune attack directed against myelin-assoiated glycoprotein.

Dexamethasone suppression test abnormalities in multiple sclerosis Relation to ACTH therapy

We studied the 1-mg overnight dexamethasone suppression test (DST) in patients with MS. In about 50% of patients, serum cortisol did not fall below 5.0 ug/dl. This percentage was similar in patients with major depression, but contrasted to 11% in normal controls. MS nonsuppressors were not more depressed than suppressors; dexamethasone bioavailability may have contributed because nonsuppressors had lower serum dexamethasone levels than suppressors. Suppressors improved in the week following ACTH therapy; nonsuppressors did not. Furthermore, serum dexamethasone values correlated positively with clinical response to ACTH treatment. The DST may be a useful neuroendocrine test of glucocorticoid sensitivity in MS patients.

Bilateral Juxtapapillary Subretinal Neovascularization Associated with Pseudotumor Cerebri

A 32-year-old obese woman with hypertension and a three-year history of pseudotumor cerebri developed bilateral juxtapapillary subretinal neovascular membranes. To our knowledge, this is the first reported case of bilateral subretinal neovascular membranes complicating the course of this disease. The subretinal neovascular membrane in the left eye spontaneously involuted, but because the membrane in the right eye threatened the foveola, the patient underwent argon-laser photocoagulation. The subretinal fluid and hemorrhage progressively resolved, the membrane was replaced by fibrous tissue, and visual acuity improved. The pathogenesis of the subretinal neovascular membranes was presumably secondary to pressure deformity of the border of Bruchs membrane at the optic disk, creating a discontinuity of normal anatomic apposition of the chorioretinal layers. This anatomic dehiscence, coupled with hypoxia created by axonal tissue swelling and resultant impaired vascular perfusion of the tissues, led to the development of subretinal neovascular membranes.

Reduced T-lymphocyte cell reactivity as a function of human aging

Abstract The mechanisms underlying reduced T-cell mitogenic reactivity which accompany human aging were explored in vitro using concanavalin A (Con A) to induce cell proliferation. Peak mitogenic reactivity of both unfractionated mononuclear cells (MNCs) and purified E + cells from elderly donors was reduced compared to the corresponding cell populations from young individuals. Flow cytometric studies demonstrated that the number of cells entered into the cell cycle at the time of maximum mitogenic stimulation was reduced in the elderly. Peak response to Con A of E + cells from young donors cocultured with monocytes from old individuals matched that obtained when these cells were cocultured with monocytes from young donors. The response to Con A of cocultures of monocytes from young donors and E + cells of old donors merely matched the reactivity of old donors MNCs. These data indicate that changes in intrinsic T-cell properties alone account for the reduced proliferative capacity in the elderly.

Lymphocyte function and the role of regulator cells in multiple sclerosis.

Although the etiology of multiple sclerosis (MS) remains unknown, evidence continues to accumulate pointing to aberrant immune function in this disease, both when the disease is active and during periods of its seeming quiescence. Classically, the immune system has been considered to be comprised of three major cell types: (1) thymus-derived lymphocytes (T cells), which are the effectors of cell-mediated immune responses; (2) bone-marrow derived lymphocytes (B cells), which act in antibody-mediated immune responses; and (3) cells of the monocyte-macrophage series. The standard classification oversimplifies the in vivo situation: Subclasses of T and B cells can now be delineated and evidence has been advanced for the existence of functional differences between macrophages harvested from different loci. The best studied of immunocyte subclasses are those of the T cells. Broadly, these can be divided into effector and regulator subgroups. Among regulator T cells are helper and suppressor subsets. The suppressor T-cell subset can be further subdivided into specific and nonspecific types. Specific suppressors are antigen triggered and suppress the response to a specific antigen. Nonspecific suppressors depress the immune response in toto. Study of specific suppressor cell function is not feasible in MS since no antigen specific for MS is known. On the other hand, nonspecific suppression can be studied in MS and, as will be shown, is markedly decreased when the disease is active. Helper T cells augment the magnitude of the immune response and suppressor T cells lessen it. At any moment the net immune response in vivo is a function of the balance between these countervailing forces. Thus, an immune response may be abrogated equally well by abolition of helper function or by augmentation of suppressor function. Given these considerations, current enthusiasm for cytotoxic immunosuppressive drugs as therapy in MS may be misdirected. Cytotoxic drugs depress both helper and suppressor cell populations and, if this occurs to a comparable extent in both cell populations, the effect on the net immune response may be zero. In animals, cyclophosphamide has been reported to selectively kill suppressor cells. 1,2 In consequence, use of this drug during flareups of MS might be contraindicated. Since MS is characterized by exacerbations and remissions, study of immune parameters which fluctuate with disease activity might offer clues t o the defect in immune regulation which permits attacks to occur or disease to progress. Manipulation-by chemical or pharmacologic means-of regulator cell functions which are abnormal when disease is active might blunt the severity of attacks of MS even while the fundamental cause of the disease itself remains unknown. The work on this problem currently being undertaken in our laboratories constitutes the theme of this paper.

Circulating suppressor cells in man as a function of age.

Abstract Concanavalin A (Con A) was used to activate suppressor cells derived from the peripheral blood of human donors. Activated suppressor cells reduced the mitogenic response of autologous peripheral blood lymphocytes (PBLs) more markedly in elderly than in young adults (72.2 ± 5.0 vs 41.8 ± 7.2%, P

Circulating immune complexes in neurologic disease

Sera from patients with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), subacute sclerosing panencephalitis (SSPE), and myasthenia gravis (MG) were assayed for immune complexes. Three techniques were used: a modified Raji cell assay, the 129-Clq polyethyleneglycol assay, and a solid-phase Clq assay. Immune complex levels were elevated in sera of some patients with MS, ALS, and SSPE, but the elevations were modest when compared with active systemic lupus erythematosus (SLE). In some cases, abnormalities were detected in only one assay system; in other cases, abnormalities were detected by two or three assay systems. In MS, immune complex elevations correlated with active disease and with decreased suppressor cell activity. Of two ALAS patients with antecedent poliomyelitis, one had markedly increased levels of immune complexes in two assays. In MG, levels of immune complexes did not differ from those of controls.

Analysis of T regulator cell surface markers and functional properties in multiple sclerosis

The relative proportions as well as cell surface and functional properties of T suppressor (T8+) and T helper (T4+) cells in peripheral blood mononuclear cells ( MNCs ) of MS patients were analyzed. The proportion of T8 cells compared to normal controls was suggestively lower in patients during relapses and significantly lower in those with progressive disease. The density of T8+ antigen on cells of MS patients with active disease as measured by median fluorescence intensity ( MFI ) was also decreased compared to controls and stable MS patients. Using OKT8-mAb modulated MNCs as a model, we found that reduction of T8 antigen density results in substantial discrepancies between FACS and microscope methods for enumeration of T8+ cells. Levels of pokeweed mitogen-induced IgG secretion by MNCs of MS patients did not correlate with proportion of T8+ cells within the MNCs , but rather with the functional activity of the T8+ cells of given individuals, as tested in an in vitro suppressor assay using constant numbers of T8+ cells.

Cellular immunity to acetylcholine receptor in myasthenia gravis Relationship to histocompatibility type and antigenic site

To debermine the nature of the cellular immune response directed against acetylcholine receptor in myasthenia gravis, we compared lymphocyte stimulation by eel receptor with clinical factors. The mean (k SEM) stimulation index wa.s 4.5 ± 0.9 for 39 myasthenic patients and 0.97 ± 0.18 for 48 controls (p < 0.001). Positive response in patients was associated with disease onset after 50 years (10 of 13 patients) and presence of thymoma (seven of eight patients), but not with HLA type. Stimulation index correlated with disease activity (rs = 0.6 3, < 0.01). Blocking the active portion of the receptor molecule with naja toxin resulted in 68 percent diminution of the response, suggesting that this site plays a significant role in the cellular immune response in myasthenia gravis.

Suppressor and cytolytic cell function in multiple sclerosis. Effects of cyclosporine A and interleukin 2.

Patients with progressive multiple sclerosis (MS) demonstrated persistent reductions in levels of concanavalin A (Con A)-induced suppressor activity and heightened levels of in vitro pokeweed mitogen (PWM)-induced IgG secretion. The reduced Con A suppressor activity could not be reversed by addition of interleukin 2 (IL-2). Cyclosporine A (CsA) treatment did not alter the defect in Con A-induced suppressor activity, but did markedly inhibit T8+ cell-mediated alloantigen directed cytolytic activity; this latter defect was reversible by in vitro addition of IL-2. CsA-treated patients did not differ from placebo-treated patients with regard to levels of PWM-induced IgG secretion or proliferative responses of their mononuclear cells to Con A. The results indicate that CsA treatment of MS patients reduces cytolytic function from baseline normal values, but does not alter aberrant suppressor cell function.