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Primary hypogammaglobulinemia describes a heterogeneous group of immunoglobulin disorders mainly composed of X-linked agammaglobulinemia, common variable immunodeficiency, and selective immunoglobulin (Ig) A deficiency. The most serious problems are related to recurrent infections with high-grade encapsulated bacteria. However, a wide variety of rheumatologic disorders also occur in association with hypogammaglobulinemic states. Septic arthritis with usual bacterial pathogens such as Staphylococcus aureus, and unusual bacteria such as Mycoplasma and Ureaplasma species, have been described in these patients. An aseptic nonerosive polyarticular arthritis that resembles rheumatoid arthritis is seen in 10% to 30% of hypogammaglobulinemic patients. Autoimmune disorders such as immune thrombocytopenic purpura, immune hemolytic anemia, juvenile rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, essential mixed cryoglobulinemia, chronic active hepatitis, and sarcoidosis have been reported in hypogammaglobulinemic patients. Finally, to complicate matters, many disease-modifying antirheumatic drugs, including gold, D-penicillamine, sulfasalazine, azathioprine, and cyclophosphamide, cause symptomatic hypogammaglobulinemia in some patients.

Gamma-globulin therapy has been practiced since the turn of the century, when clinicians used heterologous protein preparations to provide passive immunity to exposed unimmunized hosts. The need for ay-globulin preparation capable of transferring broad-based humoral immunity was recognized in the early 1950s following the description of agammaglobulinemia by Bruton. Since that time, tremendous progress has been made in the manufacturing of safe and efficacious γ-globulin products, culminating in the development of agents that can be administered intravenously. Such preparations contain a large array of antibody specificities, having been prepared from the blood of thousands of healthy donors.

At least three biochemically distinct Fcγ receptor classes have been described on human cells. These receptors have been designated FcγRI, FcγRII and FcγRIII. They are membrane glycoproteins with extracellular domains that contain immunoglobulin-like regions. Therefore, they are members of the immunoglobulin gene superfamily. They appear to be located on human chromosome 1 and may have arisen from gene duplication. All three Fcγ receptors are present on the surface of human macrophages.

The thymus, with its striking B cell infiltrates, is widely regarded as an important element in the pathogenesis of myasthenia gravis (MG) but its role remains to be elucidated. To gain further insight into the functional properties of MG thymic B cells, we studied the heavy chain isotype of immunoglobulin they produced in vitro in response to the T cell-dependent polyclonal activator pokeweed mitogen (PWM). MG thymic cells secreted prominent amounts of IgG but little IgM. In contrast, peripheral blood mononuclear cells (PBM) of the same subjects secreted similar amounts of IgG and IgM as did PBM of control subjects. In cell admixture experiments, MG thymic T cells, like PBM T cells, helped autologous PBM B cells produce IgM as well as IgG, although the overall magnitude of help for both isotypes appeared less than that of PBM T cells. Thus, in response to PWM, MG thymic B cells are largely committed to an IgG response and this likely reflects the intrinsic properties of these cells rather than the immunoregulatory properties of thymic T cells. This IgG isotype switch likely reflects in vivo activation events.

This is our second symposium on the future directions of immunoglobulin therapy. While the first symposium explored the mechanisms of action of intravenous immune globulin (IVIG) and its use in various clinical disorders, this symposium has taken a new direction in reviewing the potential therapeutic role of monoclonal antibodies in the treatment of malignancy and autoimmune diseases. It has been 16 years since K6hler and Milstein (1) successfully immortalized antibody-producing cells by fusing them with mouse myeloma cells. The ability to generate hybridoma cell lines producing a specific antibody has provided the tools which have had far-reaching implications in many areas of basic and clinical medicine. Dr. Matthew Scharff reviewed the fascinating history of monoclonal antibodies and the current state of hybridoma technology. For years scientists have been looking for " the magic bullet" for the treatment of malignant disorders. The concept of a specific immunotoxin, an extremely potent poison conjugated to a monoclonal antibody, has initiated a new era in cancer chemotherapy. Recent advances in monoclonal antibody methodologies, recombinant DNA, and gene transfer technologies have enabled scientists to genetically engineer antibody molecules with highly potent toxins. Drs. Ellen

Previous studies have shown that peritoneal inflammatory exudate cells from guinea pigs with experimental allergic encephalomyelitis proliferate prominently when cultured with the sensitizing myelin basic protein. Peripheral blood lymphocytes (PBL) obtained at the same time responded little, if at all. In the present studies, recombination experiments using appropriate mixtures of peritoneal exudate macrophages and PBL show that the presence of such macrophages will not enhance in vitro reactivity of the PBL to basic protein. The oil-induced peritoneal inflammatory response appears to deplete the PBL somewhat of antigen-reactive lymphocytes, but does not totally explain the difference in in vitro responsiveness between the lymphocytes in the peritoneal exudate and in the peripheral blood.

Monocyte and macrophage Fc gamma receptors are important components in the recognition of IgG-coated cells and IgG-containing immune complexes. Two proteins have been identified on human peripheral blood monocytes that can function as Fc gamma receptors, Fc gamma RI (70 Kd) and Fc gamma RII (40 Kd). We studied the role of Fc gamma RI and Fc gamma RII on human monocytes by examining their binding of IgG- sensitized cells (human IgG anti-D-coated RBCs and rabbit IgG- sensitized sheep RBCs) and their binding of human trimeric IgG. To examine the function of monocyte Fc gamma RII, we used an anti-Fc gamma RII monoclonal antibody (MoAb) that competes for the Fc gamma RII ligand binding site. Preincubation of monocytes with saturating concentrations of anti-Fc gamma RII MoAb did not alter the recognition of IgG (anti-D)-sensitized human RBCs by monocytes. Furthermore, ligand- binding studies demonstrated that anti-Fc gamma RII antibody altered neither the number nor the affinity of monocyte-binding sites for human IgG trimer. Anti-Fc gamma RII inhibited monocyte binding of rabbit IgG- sensitized sheep RBCs, but only at low ionic strength or temperature when increased numbers of monocyte Fc gamma RII were expressed. At low ionic strength and 4 degrees C, anti-Fc gamma RII also partially inhibited monocyte binding of human trimeric IgG. Thus, monocyte Fc gamma RII does not appear to recognize IgG-sensitized RBCs or trimeric IgG at physiologic temperatures and ionic strength. The data suggest that Fc gamma RI is the primary Fc gamma receptor on monocytes involved in the binding of IgG (anti-D)-sensitized erythrocytes and low mol wt complexes of IgG.

We have found prominent secretion of immunoglobulin and anti-acetylcholine antibodies by thymic lymphocytes (TL) of myasthenics despite a relative paucity of B (surface IgM+) cells in such TL. To determine whether there was a surface IgM- B cell in the TL which could manifest such responses, we compared the frequency of cells expressing the B cell-specific phenotypic marker CD20 (B1+), surface IgM (SIgM+), surface IgG (SIgG+), and surface IgD (SIgD+) in TL and autologous blood mononuclear cells in 36 myasthenic patients. B1+ cells were significantly more frequent than SIgM+ cells in TL (3.2 +/- 0.6 vs 0.6 +/- 0.2). In double-labeling studies, less than 25% of the B1+ cells coexpressed SIgM. Only 0.3% of the TL were SIgD+. In contrast, the frequencies of B1+ and SIgM+ cells in autologous blood were not significantly different (10.7 +/- 1.3 vs 8.2 +/- 0.8%). About 75% of blood B1+ cells co-expressed SIgM. These findings suggest that mast B cells in these TL have undergone isotope switching during prior in vivo differentiation and could manifest the observed humoral responses.

Suppressor cell function was evaluated in 11 patients with atopic dermatitis (AD) and elevated IgE levels (mean, 4,554 IU/ml ± 1,825 SEM) and compared to 11 matched nonatopic controls (135 IU/ml ± 52 SEM). Two assays were employed to evaluate suppressor cell function. In the first assay, concanavalin A-activated suppressor cell activity of AD and control subjects were compared. In the second assay, peripheral blood mononuclear cells (PBM) from the same AD and control subjects were stimulated with varying doses of mitogen at day 0 and after 24 hr of preculture. In this system, increased proliferative response of precultured cells as compared to 0-hr cells has previously been shown in normals to represent loss of suppressor cell function in vitro. The lack of such an increase implies aberrant suppressor cell function. The data from both assays showed no significant difference in the degree of suppressor cell function of the patient population vs the control population. Thus, suppressor cell function as tested in these proliferative assays appears normal in AD patients with increased IgE.

HE ABILITY to identify and remove poten­ tially dangerous foreign organisms and pro­ teins is critical to the survival of a species. In hu­ mans, IgG antibodies serve to recognize such foreign antigens and to facilitate their removal. The latter process involves the macrophage phago­ cytic system, the cells of which express Fcl' recep­ tors. These receptors specifically recognize the Fc domain of IgG antibody that coats the foreign or­ ganism. On the surface of macrophages, these Fc'Y receptors mediate cell attachment and stimulate phagocytosis. Moreover, their perturbation leads to the release of mediators of inflammation and enzymes that are involved in the pathogenesis of autoimmune diseases. At least three biochemically distinct Fcl' recep­ tors have been described on human cells, and each appears to be present on the surface of human mac­ rophages. These receptors have been designated FC'YRI (CD 64), FCI'RII (CD 32), and FC'YRIII (CD 16). They are membrane glycoproteins with extra­ cellular domains that contain immunoglobulin-like regions. Therefore, they are members of the im­ munoglobulin gene superfamily. They appear to be located on human chromosome 1 and may have arisen from gene duplication. This review focuses on the current state of knowledge of these hetero­ geneous human macrophage Fc"y receptors. FC-yRI

We investigated sequential humoral immune responses in the CSF and blood of 6 stable multiple sclerosis (MS) patients without decreases in the blood-brain barrier. Anti-tetanus toxoid antibodies (anti-TT Ab) increased to a similar relative degree within the CSF and blood starting within 2 weeks after subcutaneous booster injection of TT. In 3 of 4 subjects, CSF lymphocytes obtained at 2 weeks secreted anti-TT Ab to the same degree as autologous blood lymphocytes when cultured with pokeweed mitogen. These findings suggest a prompt antibody response within the CSF to systemically administered antigen, not due to diffusion from the serum, with active trafficking of TT-sensitized lymphocytes into the central nervous system.

Myasthenia gravis (MG) 4 is a disease of neuromuscular transmission characterized by weakness of striated muscles. The defect in neuromuscular transmission is mediated by autoantibodies which react with nicotinic acetycholine (AChR) receptors at postsynaptic myoneural junctions. In this review, we examine the immunopathogenesis of MG and consider various therapeutic strategies suggested by work in this area as well as by advances in our understanding of immunoregulation and autoimmunity.

Despite the importance of neurologic manifestations of the collagen vascular diseases, it is clear that there are more questions than answers. The use of in vitro culture systems, in vivo models, and clinical and laboratory study of patients that attempt to correlate these findings with immunologic abnormalities, including parallels with animal models, should increase our understanding of these syndromes.

The mitogenic activity of Staphylococcus aureus peptidoglycan (PG), teichoic acid (TA) and cell wall (CW, a PG-TA complex) for mouse, rat and human lymphocytes was determined by measuring DNA synthesis. At optimal concentrations PG was the most potent mitogen, inducing maximum stimulation of mouse spleen lymphocytes on day 2 of culture, rat spleen lymphocytes on day 3, rat lymph node cells on day 2, human peripheral blood lymphocytes on day 5, and human cord blood lymphocytes on day 4. CW was less mitogenic than PG for mouse splenocytes and human peripheral and cord blood lymphocytes, with maximum stimulation occurring on days 2, 6 and 5, respectively. CW was not mitogenic for rat lymphocytes, and TA was not mitogenic for mouse, rat and human lymphocytes. At high concentrations CW and TA were cytotoxic, as indicated by markedly reduced thymidine uptake and low viability. PG was not toxic to lymphocytes. Our results suggest that TA when bound to PG can at high concentrations mask the mitogenic activity of PG and render CW cytotoxic.

Staphylococcal cell wall products have been widely examined as probes for dissection of in vitro human immune responses. Mitogenic and polyclonal B-cell-activating properties have been attributed to intact cell walls or the protein A constituent thereof. We now report that staphylococcal peptidoglycan (PG), the major cell wall constituent, is not only a potent mitogen but also a polyclonal B-cell activator for human peripheral blood mononuclear cells (PBM). PG-induced proliferative responses of human PBM were comparable to that observed in pokeweed mitogen-stimulated cultures. As was true for pokeweed mitogen, PG-induced proliferation required the presence of T-cell help. Cultures of human PBM with PG also resulted in B-cell differentiation as reflected by an increase in numbers of immunoglobulin-secreting cells in stimulated cultures. In contrast to the proliferative response, PG-induced B-cell differentiation was relatively T-cell independent. This point became apparent when B-cell fractions were partially depleted of excessive numbers of monocytes before culture. Also, B-cell proliferation did not appear to be a major prerequisite for PG-induced B-cell differentiation responses. These data indicate that PG is a potent T-cell-dependent mitogen and relatively T-cell-independent polyclonal B-cell activator of human lymphocytes.

A patient with adult-onset insulin-requiring diabetes mellitus had persistent severe local reactions to all available insulins of animal origin. Skin reactions were biphasic in nature with both immediate and late characteristics. An extensive immunologic investigation of this problem was undertaken, revealing evidence of reaginic antibody involvement in the reactions. Routine histologic studies suggested the possibility that Arthus-type mechanisms played a part, although this impression was not confirmed by immunofluorescent microscopy. A program of medical management provided some relief of symptoms.

The late phase reaction (LPR), an IgE-dependent sequel to the wheal and flare response (WFR), was studied in ragweed (RW)-sensitive subjects 15 min and 6 to 8 hr after intradermal RW injection. The role of WFR in the genesis of LPR and LPR dependence on RW dose were determined by skin test titration to extinction of LPR. LPR size correlated with WFR size. LPR were noted with WFR as small as 9.5 ± 1.0 mm (S.E.M.) and RW doses as small as 0.01 protein nitrogen unit (PNU). In a group of WFR-positive but LPR-negative subjects, LPR were not induced despite increasing WFR to 18.2 ± 1.3 mm by simultaneous injection of RW + histamine (RW-H). Light microscopy of 1-µm biopsy sections of direct and Prausnitz-Kustner (P-K) LPR revealed a mixed cellular infiltrate qualitatively no different than that seen 6 hr after isolated WFR. Fibrin deposition in the absence of immunoglobulin or complement was seen by fluorescent microscopy in LPR but not in controls. These data suggest that LPR may follow small RW doses. Furthermore, the failure of RW-H injection to induce LPR argues against a gatekeeper role for WFR in the genesis of LPR. The significance of the cellular infiltrate is not clear although fibrin deposition explains the clinical induration of LPR. This fibrin deposition is evidence for activation of the coagulation system in these IgE-dependent “delayed in time” reactions.

Summary We studied the abnormal in vitro polyclonal B-cell activity observed in patients with multiple myeloma and Waldenstrom's macroglobulinaemia. Numbers of cells spontaneously secreting immunoglobulin (Ig) in freshly isolated suspensions of peripheral blood mononuclear cells and pokeweed mitogen (PWM) stimulated cultures of blood mononuclear cells were determined with a protein. A reverse haemolytic plaque assay. These data were correlated with both the clinical and laboratory parameters of disease. Furthermore, Ig secreted into supernatants of PWM-stimulated cultures was examined by a light chain radioimmunoassay for evidence of in vitro activation of malignant B-cells. The mean level of circulating immunoglobulin secreting cells (IgSC) in patients was elevated when compared to that of normal subjects. The highest values were observed in those patients with the highest levels of serum paraprotein. However, experiments with cycloheximide suggested that such increased circulating IgSC values were often caused by the detection of Ig passively adsorbed to blood mononuclear cells. The studies with PWM stimulation of blood mononuclear cells were particularly revealing. Cultures of patient blood mononuclear cells with PWM showed depressed IgSC responses as a group compared to cultures of normal blood mononuclear cells: nevertheless, approximately half the patients demonstrated a sizeable response to PWM. No evidence for preferential activation of Ig secretion by the malignant B-cell clone was observed. Impaired PWM induced responses were associated with advanced or progressive clinical disease.

Urticaria and angioedema are common problems encountered in clinical practice. The list of potential causes is quite extensive, and ruling in or out the many possibilities requires a probing history, careful physical examination, and appropriate selection of screening laboratory tests. Identification of the cause is more likely in patients who present with acute (evanescent) symptoms than in patients whose symptoms follow a chronic course. In the latter group the expertise of the subspecialty physician is often useful.

The effect of splenectomy on the induction of neonatal tolerance to histocompatibility antigens was studied. Newborn BN ( Ag-B 3 Ag-B 3 ) rats were splenectomized or sham splenectomized prior to transfer of a tolerance-inducing inoculum of Lewis/BN ( Ag-B 1 Ag-B 3 ) bone marrow cells. Twenty-two percent of the splenectomized animals were found to be highly tolerant of subsequent Lewis skin allografts, compared to 53.8% of the shamsplenectomized group. In addition seven of eight incompletely splenectomized animals were found to be highly tolerant. The relevance of these data to currently postulated mechanisms of classical neonatal tolerance induction is discussed.

Utilizing a 51Cr release cytotoxicity inhibition assay, putative anti-receptor site antisera (anti-A RSB) were assayed for their capacity to inhibit specific alloantibody, a result predicted by the recent work of Ramseier and Lindenman. Utilizing various isogenic strains of rats, anti-RS antisera prepared by injecting appropriate F1 hybrid animals (A × B) with either lymph node cells (A) or specific alloantiserum (A anti-B) were found to be inactive in this assay. It appears that the Ramseier-Lindenman phenomenon cannot be corroborated using a 51Cr release inhibition assay.

We cultured blood mononuclear cells of patients with myasthenia gravis both with and without removal of T8 suppressor cells. The levels of synthesized antibodies to acetylcholine receptor and IgG as well as the frequency of immunoglobulin-secreting cells were all higher in pokeweed mitogen–stimulated cultures depleted of T8+ cells. Thus, autologous suppressor cells within the T8+ population exert some regulatory control over anti-acetylcholine receptor–producing cells in patients with myasthenia gravis.

We characterized phenotypic and functional properties of B cell lines obtained from patients with multiple myeloma to determine how well they conform to particular stages of B cell differentiation. This information is a prerequisite for using such lines as tools for studying B cell growth and the regulation thereof. Two lines, GM1312 and GM1500, expressed B1 and Ia, determinants on early B cells, but expressed little, if any, T10, a determinant expressed on plasma cells. By contrast, B1 and Ia were poorly expressed on two other lines, GM2132 and U266. T10 was expressed on GM2132 but not on U266. Using a reverse hemolytic plaque assay, we also assessed the numbers of cells actively secreting immunoglobulin (IgSCs) in such cultures to provide a functional marker of B cell differentiation. We observed consistently higher numbers of IgSCs in cultures of GM2132 than in GM1500 and GM1312. These phenotypic and functional markers were stable over several months. The data suggest that such cell lines represent early (GM1312, GM1500) and later stages (GM2132, U266) of B cell differentiation, although all lines were derived from patients with multiple myeloma.

We have developed a microculture system to study pokeweed mitogen (PWM)-induced B-cell differentiation responses of CSF lymphocytes from patients with multiple sclerosis (MS) and other neurologic diseases (OND). B-cell differentiation was assessed by (1) enumeration of immunoglobulin-secreting cells (IgSC) by a protein A reverse hemolytic plaque assay; and (2) quantitation of supernatant IgG by ELISA. Cultures of MS CSF cells and OND CSF cells responded to PWM with a similar frequency, with responses in CSF cell cultures exceeding responses in corresponding blood cell cultures in several instances in both groups of patients. Numbers of IgSC in unstimulated cultures of MS CSF cells exceeded numbers in cultures of autologous peripheral blood mononuclear cells (PBM). Results suggest that CSF cells may be a particularly reactive population compared with PBM.

— A microtechnique was established for the study of the limited numbers of cells available in CSF. The method allowed for the determination of the number of immunoglobulin-secreting cells (IgSC) as well as the quantitation of immunoglobulin or specific antibody secreted into the culture medium. Dose-response curves and kinetic profiles for the IgSC responses induced by pokeweed mitogen (PWM), a polyclonal B cell activator, were similar for CSF cells (CSFC) and peripheral blood mononuclear cells (PBMC). When equal numbers of unstimulated CSFC and PBMC from patients with multiple sclerosis (MS) were cultured, both the number of IgSC and the amount of secreted IgG were significantly greater in CSFC cultures. The addition of PWM resulted in the differentiation of B cells among both CSFC and PBMC, as shown by an increase of both the number of IgSC and the amount of secreted IgG. Results with cultures of unstimulated cell suspensions from MS patients suggested that CSF cells from these patients may be activated in vivo. The addition of mitomycin-C treated autologous peripheral blood mononuclear cells (PBMCM) to cultures of small numbers of CSFC or PBMC resulted in an augmentation of the number of IgSC in both, whether or not they were stimulated with PWM, and also in an increased secretion of IgG into the culture supernatants. This culture system should prove useful in functional studies when limited numbers of cells are available.

A microtechnique for studying phytohemagglutinin (PHA) responsiveness of 5000 separated human peripheral blood lymphocytes is described. Cells were distributed in conical-bottom microtiter wells for 3- and 5-day culture periods, after which stimulation was measured by incorporation of tritiated thymidine into DNA. Peak stimulation occurred over a narrow PHA dose range. More pronounced PHA stimulation was noted in 5-day cultures than in 3-day cultures using this technique, while the reverse was true for standard technique (500,000 lymphocytes). This microtechnique enables one to study PHA-induced proliferation of an extremely small number of separated human lymphocytes obtained not only from blood, but also from cellular compartments where lymphocytes are found in limited quantity.

The influence of presensitization (blood transfusions) on B-cell immunity as reflected in the serum of two groups of candidates for cadaveric donor renal allografts was examined. The first group initially had a high level of panel-reactive antibody (PRA) greater than 72% but experienced a large decrease in PRA (greater than 70%) 6-34 months prior to transplantation. In contrast, the second group maintained a high PRA (100%) for up to 28 months after sensitization and before transplantation. Three blood Three blood samples from each patient, representing a maximum time span of 34 months, were analyzed. Levels of IgG, IgM isohemagglutinins, and antitetanus antibody were used as indicators of B-cell function. There were no significant differences between the individual values of a single patient with regard to each parameter. However, Group II patients had elevated values of total IgG relative to Group I patients. Total serum IgG-subclass levels (IgG1, IgG2, IgG3, IgG4) were measured and the relationship between a specific IgG subclass and the PRA activity was determined. IgG1 values in Group II were higher than those found for Group I. The other IgG subclasses were all within normal levels and were not significantly different between Group I and Group II. When IgG-subclass typing of PRA was performed, IgG1 accounted for most of the activity in both groups and a fall in PRA-specific IgG1 was associated with the reduced PRA observed in Group I. The data indicate that humoral immunity, as reflected by total and specific immunoglobulin levels, is intact in general in the two groups of presensitized renal allograft candidates examined and that any loss of PRA activity reflects a reduction in a specific immune response.

Peripheral blood lymphocyte subsets were enumerated in five children with abnormal lymphatic circulation (three with lymphangiectasia, one with chylothorax, and one child with chyloperitoneum). All patients were lymphopenic. The percentage and absolute number of blood T-lymphocytes (CD3) were low in two children and normal in the other children. The percentage and absolute number of helper/inducer lymphocytes (CD4) were markedly reduced in all patients. The percentage of suppressor/cytotoxic lymphocytes (CD8) was normal or elevated in all children, and the absolute number of CD8 cells was normal in three patients. The CD4CD8 ratio was reversed in all patients. In the two patients tested, the proliferative response of peripheral blood mononuclear cells to mitogens was reduced. T-lymphocyte subsets were measured in the pleural or peritoneal fluid of three patients, and the CD4CD8 ratio was normal or increased. In each child, the CD4CD8 ratio in the lymphatic fluids was markedly higher than the CD4CD8 ratio of the blood (4.00.45, 1.750.95, and 1.30.85). The reversed CD4CD8 ratio in the blood in cases of chronic loss of chyle may be due to either selective transport of CD4 lymphocytes into the lymphatic fluids or a shorter half-life of CD8 compared to CD4 lymphocytes. This finding may in part explain the abnormal cellular immunity previously observed in patients with lymphangiectasia.

Using a protein A-reverse hemolytic plaque assay, we found that some patients with myasthenia gravis have increased numbers of circulating immunoglobulin secreting cells (IgSC). This pattern was not related to drug therapy, age, sex, duration of symptoms, thymectomy, or serum levels of AChR antibody, although elevated IgSC values tended to occur in patients with active symptoms. The responses of peripheral blood mononuclear cells to pokeweed mitogen were normal. These data suggest increased in vivo polyclonal B-cell activation in some myasthenic patients, although in vitro polyclonal B-cell activation is normal.

We compared the percentages of thymic mononuclear cells (TMC) that bind monoclonal antibodies to T-cell subpopulations in patients with myasthenia gravis (MG) and non-MG patients undergoing cardiac surgery (CS). There were no significant differences in percentages of OKT3 + , OKT4 + , OKT6 + , or OKT8 + cells or the OKT4:OKTB ratio. There was an increase in the percentage of Ia + (immune response gene-associated antigen) TMC in MG compared with CS but no significant differences in B cells or phagocytic cells. The Ia + cells could be abnormal B cells, activated T cells, or thymic dendritic cells.

The level of circulating cells secreting IgG, IgM, and IgA (IgSC) provides insight into the degree of in vivo polyclonal B-cell activation (PBA). Patients with rheumatoid arthritis (RA) exhibit abnormalities in humoral immune responses suggestive of augmented in vivo polyclonal B-cell activation. Therefore, a protein A reverse hemolytic plaque assay was used to measure the level of circulating IgSC in 32 RA patients. The mean level of circulating IgSC in RA patients was 3602 +/- 747 (SEM) compared to a mean of 1407 +/- 443 in patients with other types of arthritis and 1253 +/- 216 (P less than 0.02) in healthy volunteers. Levels found in RA patients did not appear to reflect disease activity or concomitant corticosteroid therapy. However, a subset of RA patients receiving gold therapy had levels of IgSC (1381 +/- 501) similar to those seen in healthy volunteers (P greater than 0.5). These data are consistent with augmented in vivo polyclonal B-cell activation in RA. In addition they suggest that gold affects mechanisms controlling in vivo B-cell activation.

This article is highlighted by the finding of striking cervical lymphadenopathy in a patient with acquired hyper-IgM syndrome and the pathologic description of the involved nodes. Routine hematoxylin-eosin stains demonstrated the presence of idiopathic necrotizing granulomas in the nodal tissue, a finding not previously reported in this syndrome. Immunoperoxidase techniques were used to further characterize these granulomas and delineate the cellular composition of the nodal architecture. We found that the necrotizing granulomas consisted of a peripheral rim of la positive palisaded, epithelioid histiocytes and central areas of debris and scattered inflammatory cells that were T11 positive. In the uninvolved areas of the node, we observed a lack of IgG-bearing lymphocytes in germinal centers as well as an absence of IgG-containing and decreased IgA-containing plasma cells in interfollicular areas. In conjunction with these in situ observations, there was a lack of IgA and IgG immunoglobulin-secreting cell responses in pokeweed mitogen-stimulated cultures of the patient's peripheral blood mononuclear cells. Unique features of this article include: (1) the association of necrotizing granulomas with the hyper-IgM syndrome and (2) the use of monoclonal antibodies to characterize the distributions of nodal lymphocytes in a patient with this disorder.

Abnormalities of the thymus have long been noted in patients with myasthenia gravis (MG).1,2,3 Morphologically, the presence of germinal centers in the medulla of the MG thymus was described by Castleman in 1949.1 Functionally, the MG thymus cells have altered immunologic activity.2,3 Recently the development of monoclonal antibodies to T cell subsets allows for the furthur investigation of the MG thymus.4 We have used such monoclonal antibodies to investigate the MG thymus in tissue sections. We have compared these results to findings obtained in studies of suspended cells from the same thymus specimens.