Mechanism of demyelination in the guinea pig

Experimental allergic encephalomyelitis (EAE), accompanied by demyelinating central nervous system (CNS) lesions, can be induced in guinea pigs sensitized with whole guinea pig CNS tissue, but not in animals sensitized with purified myelin basic protein (BP). This type of chronic demyelinating EAE is presumably a result of a combination of a cell-mediated immune response to the encephalitogenic BP and a separate response to other nonencephalitogenic CNS antigens. We report here that demyelinating EAE can be induced when separate sensitizations are used to induce a cell-mediated response to BP and a second immune response to nonencephalitogenic CNS antigens. Animals sensitized in separate sites with guinea pig BP and whole chicken brain develop CNS demyelinating lesions. Animals sensitized only to BP or chicken brain do not develop demyelination. The antigen(s) responsible for demyelination are found in the myelin fraction of chicken brain.     

Study of HLA as a predisposing factor and its possible influence on the outcome of multiple sclerosis in the sanitary district of Calatayud, northern Spain.

The relationship between multiple sclerosis (MS) and the HLA antigens DR2 and DQ1 is well recognised, but, in Spain, it has not been clearly defined. The aim of our study was to investigate the relationship between MS and HLA antigens in the sanitary district of Calatayud, northern Spain, and to correlate these antigens with the progression of the disease. Thirty-four patients were selected from a long-term (October 1990 to July 1996) prospective survey in the region where there was a prevalence rate of 58 per 100,000 population. The HLA antigens were determined in 31 patients. A control group of 895 people of Caucasian race was recruited from the same population. We performed serologic tests on all participants. Nucleotide typing was carried out in DR2-positive patients. The most frequent antigens in excess in MS were: A19 (odds ratio, OR: 2.29, p = 0.04), B5 (OR: 2.85, p = 0.02), B41 (OR: 7.65, p = 0.04), CW7 (OR: 3.4, p = 0.004), DR6 (OR: 6.18, p = 0.0001) and DR10 (OR: 3.4, p = 0. 004). The DR2 antigen was also more frequent in MS patients (39%) than in controls (19%; OR: 2.69, p = 0.01). All positive DR2 patients showed the DR15(2) split but not the DR16(2) split. The frequency of antigens CW4 and DR1 was lower in MS patients than in controls. The CW4 antigen was detected in 12% of the patients and in 33% of the controls (OR: 0.28, p = 0.04). The DR1 antigen was found in 20% of the controls and in none of the MS patients (OR: undefined, p = 0.01). The DQ1 antigen was observed in 68% of the patients and in 50% of the controls (OR: 2.1, p = 0.07). We did not find any relationship between HLA antigens and progression of the disease. Although we found that DR2 antigen is linked to MS, we also found other antigens related to the disease. This suggests a genetic heterogeneity in our geographic area. We also concluded that the DR1 antigen may play a protective role, as it was detected in 20% of the controls and in none of the MS cases.     

Cellular hypersensitivity to nervous antigens in Guillain-Barré syndrome

Cell-mediated immune responses to various nervous antigens were examined in 12 cases of Guillain-Barré syndrome (GBS), 24 cases of noninflammatory peripheral neuropathy (NIPN), and 18 cases of degenerative disorders of central nervous system (CNSDD), using the lymphocyte-transformation technique. Cellular hypersensitivity to bovine P2 protein (P2) and a synthetic peptide, SP66-78, corresponding to the residues 66–78 of P2, was detected in about two-thirds of GBS cases, especially in the active or improving stages, but not in NIPN and CNSDD. The lymphocytes sensitized to these nervous antigens might play an important role in the pathogenesis of GBS.     

Histocompatibility antigens and antibodies to viral and other antigens in Alzheimer pre-senile dementia

Alzheimer's disease may arise from an interaction between a conventional infective agent and a particular disease susceptibility (related to the HLA-A or B locus). HLA antigens and antibodies to conventional infective agents were examined in 14 patients with pre-senile dementia. Most of the sample probably suffered Alzheimer's disease, though one subject may have had Pick's diseas. No particular HLA type or antibody was associated with the sample.     

Guillain-Barré syndrome and Hodgkin's disease: Three cases with immunological studies

A cell-mediated autoimmune reaction to peripheral nervous system (PNS) antigens is widely held to be important in the pathogenesis of Guillain-Barré syndrome (GBS). We report GBS in 3 patients with Hodgkin's disease in whom we were able to demonstrate partial immunosuppression using in vivo and in vitro methods. Because GBS has been associated with other conditions in which degrees of immunosuppression may ocur (organ transplantation, viral syndromes, systemic lupus erythematosus, postoperative states, and pregnancy), we suggest that under certain circumstances, partial and perhaps transient immunosuppression could serve as one contributing factor in triggering an autoimmune disease of the PNS.     

Familial autoimmune myasthenia gravis and thymoma: occurrence in two brothers

At ages 31 and 42 years, two brothers presented with clinical, pharmacologic, electrophysiologic, and immunologic characteristics of autoimmune myasthenia gravis. At thymectomy, both had histologic findings of epithelial thymoma. HLA analysis revealed A2, A3, B7, and B39 antigens in one patient and A3, A24, B7, and B40 antigens in the other. Familial myasthenia gravis with thymoma has not been described previously. Familial thymoma has been rarely reported, but never with myasthenia gravis.     

Polymyositis inpatients infected with human T-cell leukemia virus type I: The role of the virus in the cause of the disease

To investigate the mechanism of polymyositis in human T-cell leukemia virus type 1 (HTLV-I) infection, we studied 6 HTLV-I–positive patients, 3 with polymyositis and 3 with adult T-cell leukemia but without clinical signs of muscle disease, by (a) quantitative single or double immunocytochemistry on serial 4-μm-thick muscle biopsy sections using antibodies to lymphocyte subsets, major histocompatibility complex (MHC) antigens, and HTLV-I proteins; (b) polymerase chain reaction using HTLV-I primers in the RNA and DNA extrcted from 50 μg of muscle tissue or from serial 5-μm-thick fresh-frozen tissue sections; and (c) cocultures of the patients' HTLV-I–positive peripher blood lymphocytes with their homologous muscles searching for replication of HTLV-I within the myotubes. In the muscle of patients with HTLV-I–associated myopathy, the predominant endomysial cells surrounding healthy muscle fibers were CD8⁺ cells followed by CD4⁺ cells and macrophages. MHC-I antigens were ubiquitous in the muscles of all 6 patients, even in those without endomysial inflammation. HTLV-I sequences were amplified from the whole muscle biopsy specimens but the cells harboring viral antigens were rare endomysial macrophages and not muscle fibers. Although HTLV-I sequences were amplified from all the patients' peripheral blood lymphocytes, these cells did not exert myotoxicity or resulted in viral replication in cocultures with their homologous myotubes. We conclude that in HTLV-I polymyositis (a) the HTLV-I sequences amplified from the whole muscle biopsy specimens are related to scattered HTLV-I–positive endomysial macrophages; (b) HTLV-I and HTLV-I–positive lymphocytes do not infect the muscle in vivo or in vitro; and (c) the virus, which perists in tissues other than muscle, triggers the activationof autoaggressive T cells that cause a T-cell–mediated and MHC-I–restricted myocytotoxicity.     

The antibody response to Epstein–Barr virions is altered in multiple sclerosis

Infection with Epstein–Barr virus (EBV) is associated with multiple sclerosis (MS), and patients with MS have an increased antibody response to some EBV antigens. The major antigens of EBV are only partly defined. Our hypothesis is that the antibody response to EBV is altered in MS. With ELISA, we found that antibodies to EB virions were increased in both serum and CSF of MS patients. Western blots demonstrated that there are multiple different antigens recognized. The antibody response was generally higher in MS to all EBV antigens, with particularly significant increases for certain antigens. We conclude that the antibody response to EBV in MS is generally increased with altered specificity.     

In situ processing and distribution of intracerebrally injected OVA in the CNS

Drainage and retention of brain-derived antigens are important factors in initiating and regulating immune responses in the central nervous system (CNS). We investigated distribution, immunological processing and retention of intracerebrally infused protein antigen, ovalbumin (OVA), and the subsequent recruitment of CD8(+) T cells into the CNS. We found that protein antigens infused into the CNS can drain rapidly into the cervical lymph node and initiate antigen-specific immune response in the periphery. A portion of the antigens are also retained by CD11b/MAC-1(+) cells in the brain parenchyma where they are recognized by antigen-specific CD8(+) T cells.     

Hemolytic anemia associated with intravenous immunoglobulin

Intravenous immunoglobulin (IVIg) is a useful tool in the treatment of a variety of neuromuscular disorders. Though IVIg therapy is generally safe, hemolytic anemia is a potentially serious complication that is often overlooked, and is currently not listed in product inserts. We analyzed 45 patients who received IVIg therapy, including 38 consecutive patients who received IVIg over a 13-month period. On 42 patients, direct antiglobulin testing was performed, searching for antibodies to the patients' own blood type. Of these 42 patients, 12 developed passive sensitization with antibodies to their own blood group antigens after receiving IVIg. Of these 12 patients, 11 patients developed hemolysis severe enough to lower the hemoglobin level by at least 1 g/dL. Of these patients, 3 required blood transfusion, and 1 had IVIg therapy truncated because of the hemolysis. Antibodies to blood group antigens are found in all commercial preparations of IVIg. Though most patients do not have clinically significant hemolysis, clinicians should be aware of this potentially serious complication. Careful monitoring of hemoglobin levels during IVIg therapy is recommended. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20:1142–1145, 1997     

Resistance and susceptibility to experimental autoimmune neuritis in Sprague-Dawley and Lewis rats correlate with different levels of autoreactive T and B cell responses to myelin antigens

Experimental autoimmune neuritis (EAN) is a CD4⁺ T cell-mediated, inflammatory demyelinating disease of the peripheral nervous system (PNS) that serves as a model for Guillain-Barré syndrome (GBS) in humans. Various mouse and rat strains show different susceptibilities to EAN that can be induced by immunization with bovine PNS myelin (BPM) + Freund's complete adjuvant (FCA). We examined PNS-induced T and B cell responses and cytokine protein production as well as mRNA expression to study the mechanisms behind susceptibility to EAN in Lewis rats and resistance in Sprague-Dawley (SD) rats. Lewis rats with EAN have elevated PNS myelin-reactive interferon-γ (IFN-γ) production, TNF-α mRNA expression, and increased B cell responses to PNS myelin antigens, but low PNS myelin-reactive transforming growth factor-β (TGF-β) and interleukin (IL)-10 mRNA expression in lymph node mononuclear cells (MNC). In contrast, resistance to EAN in SD rats is associated with reduced BPM and P2 peptide-reactive IFN-γ production, TNF-α mRNA expression, and suppressed B cell responses to PNS myelin antigens as well as up-regulation of TGF-β and IL-10 mRNA expression. Resistance to EAN is also associated with low-grade inflammation or absence of histological evidence of EAN. These results suggest that differential autoreactive T and B cells responses to PNS myelin antigens are strain specific, and the susceptibility to EAN is related to quantitative rather than qualitative differences in distribution between pro-inflammatory and anti-inflammatory cytokines. J. Neurosci. Res. 54:373–381, 1998. © 1998 Wiley-Liss, Inc.     

Vacuolar myositis with expression of both MHC class I and class II antigens on skeletal muscle fibers.

We describe here a 10-year-old patient with high levels of serum IgE and inflammatory myopathy whose muscle fibers exhibit excessive autophagy. Previous studies have demonstrated surface expression of class I MHC antigens on muscle fibers from patients with inflammatory myopathy. The muscle fibers of this patients showed marked expression of both class I and class II MHC antigens. The reaction products were demonstrated not only on sarcolemma but also in and around some vacuoles. Both CD4-positive and CD8-positive T-lymphocytes were noted in inflammatory exudates surrounding these fibers but B-lymphocytes were rare. We hypothesize that myocyte expression of both class I and class II antigens may play a role in the pathogenesis of this new type of inflammatory myopathy.     

Clinical sub-groups of multiple sclerosis in relation to HLA: DR alleles as possible markers of disease progression

We have examined the distribution of HLA antigens in 70 multiple sclerosis (MS) patients divided in three groups defined according to clinical criteria: benign MS, severe MS, cerebellar MS. We have found a significant association between severe MS and HLA-DR2, and between benign MS of more than 15 years of evolution and HLA-DR3. We review previous work along the same line and conclude that the association of HLA antigens with "clinical subgroups of MS" could indicate a genetically based heterogeneity of the disease and offer help in establishing a prognosis.     

Antibody-mediated remyelination: relevance to multiple sclerosis

Intravenous immunoglobulin (IVIG) is widely used for treatment of autoimmune neurological disorders and is currently in clinical trials as a therapy for multiple sclerosis. We have previously demonstrated that certain mouse monoclonal antibodies of the IgM isotype, promote significant remyelination when administered to mice with chronic Theiler's murine encephalomyelitis virus-induced demyelinating disease. These IgM antibodies bind to antigens expressed on oligodendrocytes. We now demonstrate that polyclonal human IgG (IVIG) and polyclonal human IgM also promote remyelination in this system. Although both polyclonal human IgG and IgM promote remyelination, IgM is more potent. Polyclonal human IgM also differs from human IgG in its ability to bind strongly to antigens expressed in the CNS and by oligodendrocytes. We propose that polyclonal IgG and polyclonal IgM may function to promote remyelination by different mechanisms. IVIG may function based on its immunomodulatory activity, while the activity of IgM is critically dependent upon its reactivity with CNS antigens. This possibility has clear relevance to the use of antibodies as a therapy for multiple sclerosis, suggesting that combined treatment with antibodies exerting immunomodulatory activity, in concert with antibodies that function through direct binding to CNS antigens, may synergize to enhance the efficacy of the therapy.     

Transplantation of a temperature-sensitive, nerve growth factor-secreting, neuroblastoma cell line into adult rats with fimbria-fornix lesions rescues cholinergic septal neurons

The HT4 cell line was derived from infection of a mouse neuroblastoma cell line with a retrovirus that encoded the temperature-sensitive (ts) mutant of SV40 large T antigen. At nonpermissive temperature, HT4 cells differentiated with neuronal morphology, expressed neuronal antigens, synthesized nerve growth factor (NGF) mRNA, and secreted biologically active NGF in vitro. We sought to establish whether transplanted HT4 cells expressed class I major histocompatibility complex (MHC) antigens, a partial requirement for recognition by cytotoxic T lymphocytes (CTL), and thus be susceptible to xenograft rejection. Differentiated HT4 cells expressed marginally detectable levels of class I MHC antigens, but demonstrated higher levels of class I MHC expression after treatment with interferon-gamma. However, HT4 cells were resistant to direct lysis by perforin, the pore-forming protein of CTLs, and thus may have potential use in xenograft experiments. To address whether HT4 cells secrete NGF in vivo, HT4 cells were transplanted into adults rats with unilateral fimbria-fornix transections. A ts cell line derived from P4 cerebellum, BT1, that does not differentiate with neuronal phenotype or synthesize NGF in vitro, was transplanted as a control. Six weeks posttransplant. HT4 cells had integrated into host CNS without forming tumors. In BT1 transplants, the number of medial septal acetylcholinesterase (AChE)-positive cells was reduced to 26-39% of the contralateral control side, depending on the rostrocaudal level. In HT4 transplants, the number of cholinergic septal neurons was 58-78% of the contralateral side. This percentage was significantly (P less than 0.005) greater than that seen with BT1 transplants, indicating that transplanted HT4 cells secrete NGF in vivo and rescue cholinergic septal neurons following fimbria-fornix transection.     

Selective decline in cellular immune response to varicella-zoster in the elderly

The incidence of herpes zoster rises markedly in the aged. We evaluated the hypothesis that cellular immunity to varicella-zoster (VZ) viral antigens may be impaired in aged subjects. We found that the lymphocyte proliferation to VZ antigen was less in older asymptomatic individuals than in normal young controls. In contrast, responses to other antigens did not differ. Antibody titers to VZ were similar in both young and old subjects. Impairment of cellular immunity to VZ, on a population basis, may contribute to the increased risk of herpes zoster in the elderly.     

HLA and anti-GQ1b IgG antibody in Miller Fisher syndrome and Guillain-Barré syndrome

We investigated serological human leukocyte antigen (HLA) types in patients with histories of Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) with ophthalmoplegia, in whom serum anti-GQ1b IgG antibody was present during the acute phase. We examined class I antigens (A, B and C) in 32 patients and class II antigens (DR and DQ) in 30, but found no association. We conclude that particular serologically defined HLA types are not preferred for the immunoresponse of anti-GQ1b IgG antibody in MFS and GBS.     

Expression of immune‐modulatory molecules HLA‐G and HLA‐E by tumor cells in glioblastomas: An unexpected prognostic significance?

The role of nonclassical human leukocyte antigens G and E (HLA‐G and HLA‐E) was originally thought to be restricted to the protection of the fetus from a maternal allorecognition. Now it is known that HLA‐G and HLA‐E exert multiple immunoregulatory functions. A prognostic significance of the expression of HLA‐G and HLA‐E by neoplastic cells in glioblastoma is not well characterized. In this study, we evaluated the expression of HLA‐G and HLA‐E by neoplastic cells in 39 cases of glioblastoma. We found the production of HLA‐G and HLA in a majority of cases. There was an unexpected positive correlation between the expression of HLA‐E and length of survival. We speculate that the expression of this molecule by neoplastic cells may represent a coincidental selective pro‐host advantage related to better response to subsequent therapeutic modalities. Mechanisms of glioblastoma cell pathophysiology and mechanisms of responses to therapeutic interventions in respect to the expression of these molecules deserves further study.     

Suppressor cell activity in multiple sclerosis

Patients with multiple sclerosis and matched controls were tested for lymphocyte stimulation response and induction of suppressor cell activity in response to concanavalin A (Con A) and antigens from axolemma or myelin. Of 17 stable patients, 6 failed to have a suppressor cell response activated by one of these brain cell antigens. Among the patients who lacked these suppressor responses, five had lymphocyte stimulation responses to the same antigens. All matched controls except for one had suppressor cell responses to these antigens and none responded with a positive cellular immune reaction. We found no difference in lymphoproliferative responses to Con A in patients and controls. The level of suppressor cell activity induced by Con A in the stable MS patients varied but did not differ significantly from that of controls.