Mapping genes regulating lymphocyte function: correlations with autoimmunity?
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Animals↗
Biomedical subjects
D Kono
Publications and source records attributed to D Kono.
Polyclonality and multispecificity of the CTL response to a single viral epitope.
The molecular anatomy of an immunodominant, Ld restricted CTL epitope located between residues 28-39 in hepatitis B surface Ag was defined to explore the immunologic constraints on mutational escape from the CTL response during a viral infection. Using a panel of hepatitis B surface Ag residue 28-39-specific CTL clones, the response to this epitope was found to be extremely diverse at the level of TCR fine specificity and beta-chain usage. Although each clone recognized shared as well as unique residues within the epitope as TCR contact sites, even the shared residues were recognized differently by different TCRs. Despite these differences, all clones were comparably cytolytic following Ag stimulation and produced similar amounts of antiviral cytokines previously shown to inhibit HBV replication. These results demonstrate that the CTL response to individual viral epitopes can be markedly polyclonal and multispecific, such that mutational inactivation of a single TCR contact site will not usually lead to viral escape from all CTL clones of the same epitope specificity. Given these constraints and the fact that the CTL response is usually directed against several different epitopes during most viral infections, mutational inactivation of a single epitope is not likely to be sufficient to cause viral persistence.
Amino Acid Substitution↗
Regulation of CD4 T cell reactivity to self and non-self.
While the thymus may be effective in inducing tolerance to lymphoid associated antigens, it is not as efficient in deleting T cells reactive to peripheral tissue specific antigens. Therefore, to maintain self tolerance to peripheral tissues, post-thymic mechanisms must be invoked. One important way to prevent autoimmune pathology mediated by autoreactive CD4 T cells is the diversion of clones to regulatory Th2 effector cells. However, many different factors contribute in vivo to the decision of stimulated CD4 T cells to develop into Th1 versus Th2 cells. For example, T cell signaling pathways may influence the types of cytokines produced by naive T cells, and studies have provided evidence for a genetic polymorphism among common mouse strains that can significantly influence the early cytokine production in stimulated naive CD4 T cells. The allele carried by the BALB/c strain promotes IL-4 production, and consequently provides resistance to autoimmune diabetes in our transgenic mouse model. In addition, antigen presenting cells can influence the development of stimulated CD4 T cells in part through the production of cytokines such as IL-12. The absorption of IL-12 in vivo can permit the expansion of Th2 type effector cells, and this phenomenon will also protect mice from autoimmunity. Finally, the relative potency of various class II positive antigen presenting cell types can influence the development of autoreactive T cells, with dendritic cells apparently being the strongest stimulator of Th1 responses. Consistent with this notion, a relB knockout mouse, which is missing dendritic cells, appears to drive Th2 development even in response to viral infection. In sum, these various influences over the Th1/Th2 decision in vivo may provide new targets for immunotherapy of autoimmune diseases.
Animals↗
Genomic composition and allelic polymorphisms influence V beta usage by the Mycoplasma arthritidis superantigen.
The Mycoplasma arthritidis superantigen (MAM) is produced by an organism that causes systemic disease in rodents leading to chronic proliferative arthritis. MAM is a typical superantigen that requires presentation to T cells by MHC molecules without processing and T cell recognition of MAM occurs through the V beta chains of the TCR. Several major findings are presented here. First, different MAM-MHC class II isotype complexes may engage different sets of V beta TCR. Thus, activation of V beta 6- and V beta 8.3-bearing T cells is more dependent upon the I-E molecule of the murine H-2 MHC than is activation of cells bearing the V beta 5.1, 8.1, and 8.2 TCR. Secondly, both genomic composition and allelic polymorphisms at the V beta chain segment of the TCR exert profound effects upon the pattern of V beta that are used by MAM. Thus, in V beta b haplotype mice, MAM engages V beta 5.1, 6, and the V beta 8 family of TCR whereas in V beta a (C57BR) and V beta c (RIIIS) haplotype mice that lack various combinations of these V beta, activation of cells bearing V beta 1, 3.1, 7, and 16 can be demonstrated. These differences in V beta usage by MAM appear to be caused by both differences in the avidity of MAM for the various V beta s and to structural allelic polymorphisms in these V beta. Clonal expansion of specific V beta in vivo after injection of MAM is also dependent upon the genomic composition of the mice, because expansion of the V beta 8 TCR seen in V beta b haplotype mice (B10.RIII) whereas marked expansion of V beta 6 is seen in V beta a mice (C57BR). In as much as these TCR have been implicated in a number of experimental autoimmune diseases, MAM may represent an ideal model to evaluate the role of superantigens in the triggering of autoimmune disease.
Alleles↗
Encephalitogenic T cells in the B10.PL model of experimental allergic encephalomyelitis (EAE) are of the Th-1 lymphokine subtype.
T helper cells reactive to myelin basic protein are clearly implicated in the pathogenesis of murine EAE. We have developed a T cell line, BML-1 that (1) is reactive to the encephalitogenic amino terminal nonapeptide (1-9NAC) of MBP, (2) is I-Au restricted, and (3) induces relapsing EAE in B10.PL (H-2u) mice. Measurement of the lymphokine profile of BML-1 revealed secretion of IL-2, interferon-gamma and lymphotoxin but not IL-4. This profile is consistent with the Th1/DTH subtype. Coculture of BML-1 with MBP-primed B cells shows that BML-1 does not provide significant helper function in vitro. In addition, BML-1 secretion of interferon-gamma was found to inhibit LPS-induced anti-MBP antibody responses. This suggested that anti-MBP antibodies may not be necessary for induction of EAE. Sera from mice, in which severe disease was induced with the 1-9NAC peptide and Bordetella pertussis, showed no development of serum antibodies to MBP. These data show that MBP-reactive Th cells of the Th-1/DTH subtype can induce EAE and do not provide Th function for anti-MBP responses and that serum anti-MBP antibodies are not found in peptide 1-9NAC-induced disease. T cell lines specific for encephalitogenic epitopes and characterized for lymphokine secretion will provide a useful tool for understanding the role of T cells in the induction of EAE.
Animals↗
A study of the specificity of the direct binding between bacteria and HLA antigens.
In the first step of the present study we re-examined the question whether HLA class I molecules isolated from human lymphocytes can bind to intact bacteria. HLA antigens were isolated from the lymphoblastoid cell line HOM-2 and incubated with the bacteria Yersina enterocolitica. Significant binding of antigens to the bacteria was detected whether the antigens were solubilized in the detergent NP 40, reconstituted in liposomes or presented as papain cleaved molecules. Next, we studied the specificity of the binding. We compared the ability of NP 40 solubilized HLA antigens derived from four different cell lines, expressing different HLA-A, -B and -C antigens, to bind to nine different strains of bacteria. Remarkably, few differences were found in that each strain of bacteria bound 10-30% of the HLA antigens derived from any of the four cells lines. Further, after a sample of HLA antigens had been incubated with one strain of bacteria, the unbound HLA antigens would fail to bind to another strain. The conclusions are as follows. First, we have confirmed a previous report that HLA class I antigens could bind to bacteria. Second, binding to bacteria is mediated through the extracellular portion of the HLA molecules which is not affected by papain cleavage. Third, it is the non-polymorphic areas of the HLA antigens which are responsible, because antigens purified from cell lines with different HLA-A, -B and -C allotypes have similar binding ability. Lastly, the binding of bacteria to HLA antigens is a universal phenomenon which does not distinguish one strain of bacteria from another.
Bacteria↗
Syndromes of toluene sniffing in adults.
Clinical and laboratory findings in 25 adults, ages ranging from 18 to 40 years, who were hospitalized for problems related to paint sniffing are presented. All but one were chronically unemployed. Three different patterns of symptoms led to hospitalization: muscle weakness (n = 9), gastrointestinal complaints including abdominal pain and hematemesis (n = 6) and neuropsychiatric disorders including altered mental status, cerebellar abnormalities, and peripheral neuropathy (n = 10). Hypokalemia (n = 13), hypophosphatemia (n = 10), hyperchloremia (n = 22), and hypobicarbonatemia (n = 23) were common. The average serum potassium and phosphorus concentrations of 1.7 mmol/L and 1.5 mg/dL were significantly lower in the muscle weakness group than in the other two groups. Rhabdomyolysis occurred in 10 patients. Hyperchloremic acidosis was found in 19 of 22 patients evaluated. The muscle weakness and gastrointestinal syndromes resolved within 1 to 3 days with abstinence from sniffing and repletion of fluid and electrolyte stores. Inhalation of paint or glue vapors should be considered in the differential diagnosis of the symptoms and laboratory findings described above.
Adolescent↗
The association of submucous cleft palate and clefting of the primary palate.
478 records of patients with cleft palate were reviewed to determine the prevalence and significance of submucous cleft palate associated with clefting of the primary palate. The prevalence of submucous cleft palate in the 71 patients with clefts of the primary palate (SMCP-CL) was 13 per cent. This is two to three times greater than the prevalence of isolated submucous cleft palate found in cleft palate clinic patients. Patients with SMCP-CL often had the symptoms of velopharyngeal incompetence (VPI) and middle ear disease. The increased prevalence of SMCP and frequent symptomatology of patients with clefting of the primary palate make it essential that patients with cleft lip have early, thorough evaluation for SMCP. Early detection of SMCP associated with cleft lip and close follow-up permits the prevention of ear problems and the proper management of VPI should it develop.
Child, Preschool↗