Peter Hjelmström

Expression of the B Cell‐Attracting Chemokine CXCL13 in the Target Organ and Autoantibody Production in Ectopic Lymphoid Tissue in the Chronic Inflammatory Disease Sjögren's Syndrome

Sjögrens syndrome is an autoimmune disease characterized by lymphocytic infiltrates resembling secondary lymphoid organs in salivary glands. In this study, we demonstrate the expression of the lymphoid tissue homing chemokine CXCL13 (BCA‐1/BLC), which has attracting properties for B cells and subsets of activated T cells, in salivary glands of patients with Sjögrens syndrome using immunohistochemistry and in situ hybridization. CXCL13 expression was primarily observed in epithelial cells in acini and ducts of inflamed glands while its receptor, CXCR5 (BLR‐1), was expressed on the infiltrating mononuclear cells. In addition, cells producing antibodies against one of the major autoantigens in Sjögrens syndrome, Ro 52, were identified at the periphery of the follicular infiltrates indicating that the ectopic lymphoid tissue is directly involved in the disease process. Identification of CXCL13 and CXCR5 in salivary glands suggests that the target organ plays an essential role in the inflammatory process by recruiting B and T cells. These results also provide a molecular mechanism by which lymphoid neogenesis and ectopic germinal centre formation might occur in the glands of these patients, which may be the key step in the development of the chronic inflammatory process in Sjögrens syndrome.

Polymorphism in tumor necrosis factor genes associated with myasthenia gravis

The aim of this study was to analyze associations between myasthenia gravis (MG) and polymorphisms in the tumor necrosis factor (TNF) region in 79 Swedish patients and 155 unrelated controls. The frequency of the TNFa2 allele of a microsatellite located 3.5 kb upstream of the lymphotoxin alpha (LT-alpha) gene in the TNF region was found to be increased in overall MG patients compared to controls. The frequency of the short 5.5 kb fragment (TNFB * 1) of a bi-allelic NcoI RFLP polymorphism located at the first intron of the LT-alpha gene was increased in patients with an early onset of disease compared to patients with a later onset.

Different HLA-DQ are positively and negatively associated in Swedish patients with myasthenia gravis

The aim of this study was to determine the association between HLA-DQ and myasthenia gravis (MG) in 79 Swedish patients and 155 unrelated population based controls. HLA genotyping was done using polymerase chain reaction combined with sequence specific oligonucleotide probes. The DQB allele, DQB1*0201 was positively associated with MG, 39/79 (49%) patients and 43/152 (28%) controls (OR 2.47, Pc = 0.037). DQB1*0201 was observed more frequently in patients with an early onset of disease, below 30 years (Pc = 0.033). A negative association was found for DQA1*0103, 7/78 (9%) patients and 38/154 (25%) controls (OR 0.30, Pc = 0.037). DQA1*0501-DQB1*0201 and DQA1*0201-DQB1*0201 together was significantly increased in patients when compared to controls (OR 2.68; Pc = 0.019). In conclusion, two different DQ2 haplotypes (DQA1*0501-DQB1*0201 and DQA1*0201-DQB1*0201) were positively and the DQA1*0103 allele was negatively associated with MG. Susceptibility and resistance to MG in Swedish patients is mediated by HLA-DQ.

Polymorphic amino acid domains of the HLA-DQ molecule are associated with disease heterogeneity in myasthenia gravis

The association between myasthenia gravis (MG) and polymorphic amino acid domains in the HLA-DQ molecule was studied in 79 Swedish patients and 155 unrelated, population-based controls. A domain unique for DQB1*0201 was positively associated in MG patients with thymic hyperplasia or an early disease onset, and two domains with residues common to DQA1*01 alleles or DQB1*05 and DQB1*06 alleles were negatively associated in patients with thymic hyperplasia or an early disease onset. Our results suggest that MG associated with thymic hyperplasia and thymoma differ in their HLA-DQ association and thus are likely to have different pathogenic mechanisms.

Increased Soluble 4‐1BB Ligand (4‐1BBL) Levels in Peripheral Blood of Patients with Multiple Sclerosis

4‐1BB ligand (4‐1BBL; CD137L) is a member of the tumour necrosis factor superfamily expressed primarily on antigen presenting cells such as B cells, macrophages and dendritic cells. Its engagement with the receptor 4‐1BB (CD137) has been shown to promote T‐cell activation and regulate proliferation and survival of T cells. The role of the costimulatory molecule in multiple sclerosis (MS) remains unclear. In this study, the expression of 4‐1BBL and soluble 4‐1BBL (s4‐1BBL) protein levels were analysed in peripheral blood of MS patients. Compared with healthy controls, MS patients had an increase in both plasma s4‐1BBL protein levels and expression of 4‐1BBL in CD14+ monocytes. In contrast, myelin basic protein‐reactive T‐cell proliferation was not found to be inhibited by the use of an anti‐4‐1BBL antibody. The elevated s4‐1BBL protein levels in the MS patients may function as a self‐regulatory mechanism of 4‐1BB/4‐1BBL interaction and costimulation.

Decreased 4‐1BB expression on CD4+CD25high regulatory T cells in peripheral blood of patients with multiple sclerosis

As a tumour necrosis factor receptor superfamily member, 4‐1BB (CD137) is preferentially expressed in CD4+CD25+ regulatory T cells (Tregs) and has been suggested to play an important role in regulating the generation or function of Tregs. Recent studies of human Tregs have shown that blood CD4+CD25high T cells were much closer to Tregs in terms of their functionality. Furthermore, CD4+CD25high Tregs have been found to have a decreased effector function in patients with multiple sclerosis (MS). In this study, we examined the expression of 4‐1BB and soluble 4‐1BB (s4‐1BB) protein levels in the peripheral blood of MS patients. Compared with healthy controls, MS patients had decreased 4‐1BB expression in their CD4+C25high Tregs and increased plasma s4‐1BB protein levels. Moreover, the plasma s4‐1BB levels of MS patients were shown to be inversely correlated with the 4‐1BB surface expression of CD4+CD25high Tregs. The down‐regulated 4‐1BB expression on CD4+CD25high Tregs of MS patients may be involved in the impaired immunoactivity of these Tregs. The elevated s4‐1BB levels may, at least in part, function as a self‐regulatory attempt to inhibit antigen‐driven proliferation of Tregs or their immunosuppressive activity.

Structural differences between HLA-DQ molecules associated with myasthenia gravis characterized by molecular modeling

Myasthenia gravis (MG) is characterized by muscle weakness due to autoimmunity against the nicotinic acetylcholine receptor (nAChR). MG is associated with polymorphisms in HLA-DQ genes and the aim of the present study was to characterize structural differences in the peptide binding groove of HLA-DQ molecules positively and negatively associated with MG. Three dimensional models of the positively associated DQ2 (DQB1*02) and negatively associated DQ6 (DQB1*0603) molecules were constructed by homology modeling techniques. The differences in peptide binding properties were primarily localized to peptide-anchor pockets P7 and P9, which might be of importance for the binding of disease-associated peptides from the nAChR.

Enhanced plasma levels of LIGHT in patients with acute atherothrombotic stroke.

Objectivesu2002–u2002 As a member of the tumor necrosis factor superfamily (TNFSF), LIGHT (TNFSF14) was recently found to be associated with platelets and released upon activation. Increased plasma levels of LIGHT have been reported in patients with myocardial infarction and unstable angina. The aim of the study was to analyze plasma levels of LIGHT in acute ischemic atherosclerotic stroke.