Biomedical subjects

J McCluskey

Publications and source records attributed to J McCluskey.

At least 19 recordsLinked to original sources

PubMed2006

Donor methylenetetrahydrofolate reductase genotype is associated with graft-versus-host disease in hematopoietic stem cell transplant patients treated with methotrexate.

Methotrexate (MTX), used as a graft-versus-host disease (GvHD) prophylactic agent in hematopoietic stem cell transplantation (HSCT), exerts its effect via folate cycle inhibition. A critical enzyme involved in folate metabolism is 5,10-methylenetetrahydrofolate reductase (MTHFR). We examined the association of a single nucleotide polymorphism (SNP) at position 677 in the MTHFR gene on GvHD outcomes in allogeneic HSCT patients administered MTX. MTHFR genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on 193 HSCT patients and donors. A total of 140 patients were transplanted with an HLA-matched related donor and 53 with an unrelated donor. GvHD outcomes were compared between genotypes by univariate and multivariate analysis. The combined donor 677CT and TT genotypes were associated with a decreased incidence of GvHD (acute and chronic combined) in HSCT recipients with an HLA-matched related donor (75% at 1 year in the CT and TT group compared with 91% in the wild type CC group, P=0.01), increased time to onset of first GvHD (P=0.001) and time to first GvHD treated with systemic therapy (P=0.022). Unrelated donor MTHFR genotype was not associated with outcome parameters and no associations of recipient genotype in either related or unrelated donor cohorts were observed.

Adolescent↗

PubMed2006

Neo-epitopes are required for immunogenicity of the La/SS-B nuclear antigen in the context of late apoptotic cells.

Mechanisms responsible for the induction of anti-nuclear autoantibodies (ANA) following exposure of the immune system to an excess of apoptotic cells are incompletely understood. In this study, the immunogenicity of late apoptotic cells expressing heterologous or syngeneic forms of La/SS-B was investigated following subcutaneous administration to A/J mice, a non-autoimmune strain in which the La antigenic system is well understood. Immunization of A/J mice with late apoptotic thymocytes taken from mice transgenic (Tg) for the human La (hLa) nuclear antigen resulted in the production of IgG ANA specific for human and mouse forms of La in the absence of foreign adjuvants. Preparations of phenotypically healthy cells expressing heterologous hLa were also immunogenic. However, hLa Tg late apoptotic cells accelerated and enhanced the apparent heterologous healthy cell-induced anti-La humoral response, while non-Tg late apoptotic cells did not. Subcutaneous administration of late apoptotic cells was insufficient to break existing tolerance to the hLa antigen in hLa Tg mice or to the endogenous mouse La (mLa) antigen in A/J mice immunized with syngeneic thymocytes, indicating a requirement for the presence of heterologous epitopes for anti-La ANA production. Lymph node dendritic cells (DC) but not B cells isolated from non-Tg mice injected with hLa Tg late apoptotic cells presented immunodominant T helper cell epitopes of hLa. These studies support a model in which the generation of neo-T cell epitopes is required for loss of tolerance to nuclear proteins after exposure of the healthy immune system to an excess of cells in late stages of apoptosis.

Adjuvants, Immunologic↗

PubMed2006

Humanized transgenic mice expressing HLA DR4-DQ3 haplotype: reconstitution of phenotype and HLA-restricted T-cell responses.

Many autoimmune conditions have close genetic linkages to particular human histocompatibility leukocyte antigen (HLA) class II genes. With the aim of establishing a murine model of autoimmune disease, we have generated an HLA DR4-DQ3 haplotype transgenic (Tg) mouse that expresses a 440-kb yeast artificial chromosome harbouring DRA, DRB1*040101, DRB4*010301, DQA1*030101, DQB1*0302 and all the internal regulatory segments. This Tg mouse line was crossed to human CD4 (hCD4) Tg mice and endogenous class II knockout mice (I-A(o/o) and I-E(o/o)) lines to generate a DR4-DQ3.hCD4.IAE(o/o) Tg line. The Tg DR and DQ molecules are expressed on the physiological cell types in these animals, i.e. on most B cells (>85%), dendritic cells (DCs) and macrophages but not on T cells, with levels of expression comparable with those of human B cells (where DR > DQ expression). The DR4/DQ3 transgenes fully reconstituted the CD4 T-cell compartment, in both the thymus and the periphery, and the analysis of the T-cell receptor repertoire in the Tg mice confirmed that these class II molecules were able to mediate thymic selection of a broad range of Vbeta families. HLA DR4- and DQ3-restricted T-cell responses were elicited following immunization with known T-cell determinants presented by these molecules. Furthermore, the DR4-DQ3-restricted CD4(+) T cells conferred protective antibody-mediated immunity against an otherwise lethal infection with Salmonella enterica var. typhimurium. These new DR4-DQ3 Tg mice should prove to be valuable tools for dissecting the importance of this class II haplotype in autoimmune disorders like rheumatoid arthritis.

Animals↗

PubMed2004

A two-component system that controls the expression of pneumococcal surface antigen A (PsaA) and regulates virulence and resistance to oxidative stress in Streptococcus pneumoniae.

Recent genomic-based studies have identified 13 two-component signal transduction systems (TCS) in Streptococcus pneumoniae. Bacterial TCSs are important for regulating expression of bacterial genes, including those which are important to the virulence of pathogenic bacteria. We have used virulence assays together with microarray analysis to investigate the importance of pneumococcal TCS04 in the virulence and gene regulation of this pathogen. Deletion mutants of the response regulator of TCS04, rr04, were examined in three independent pneumococcal strains representing three different pneumococcal serotypes. Analysis of the virulence of the three strains enabled us to identify a serotype-specific attenuation of virulence due to deletion of rr04. Microarray comparison of the transcriptional profiles of the wild-type strains with the rr04 mutants allowed us to determine which transcriptional changes were occurring in the rr04 mutants. Virulence-associated changes were demonstrated in the attenuated strain with significant downregulation of a previously determined virulence locus, psaB, psaC and psaA.

ATP-Binding Cassette Transporters↗

PubMed2003

Novel strategy for identification of candidate cytotoxic T-cell epitopes from human preproinsulin.

We describe a strategy for identifying ligands of human leukocyte antigen (HLA) class I molecules based on a peptide library-mediated in vitro assembly of recombinant class I molecules. We established a microscale class I assembly assay and used a capture ELISA to quantify the assembled HLA-peptide complexes. The identity of the bound ligands was then deduced by mass spectrometry. In this method, HLA complexes assembled in vitro in the presence of components of a mixture of peptides were immunoprecipitated and the bound peptide(s) identified by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry. This process of epitope extraction is robust and can be used with complex mixtures containing in excess of 300 candidate ligands. A library of overlapping peptides representing all potential octamers, nonamers and decamers from human preproinsulin was synthesized using unique library chemistry. Peptides from the library were used to initiate assembly of recombinant HLA-B8, HLA-B15 and HLA-A2, facilitating the identification of candidate T-cell epitopes from preproinsulin.

Epitopes, T-Lymphocyte↗

PubMed2003

Biology and functions of human leukocyte antigen-G in health and sickness.

In 1998, the first International Conference on human leukocyte antigen-G (HLA-G) was held in Paris. At that time, HLA-G was still a new HLA class I molecule, few aspects of its immunological functions were known, and its expression by tumors was just being described. In 1998, tools to properly study HLA-G were lacking, especially monoclonal antibodies, and three conclusions were drawn after the congress: (i) animal models were needed, (ii) the biology of HLA-G isoforms had to be confirmed, and (iii) HLA-G expression by tumors required clarification. Five years later, these three issues have been addressed. HLA-G is now gaining pace and is investigated for its immuno-inhibitory functions in the context of multiple pathologies. Eighty five oral presentations were given this year for more than 200 investigators working on HLA-G by speakers from over 20 countries. The success of the 3rd International Conference on HLA-G reflects the interest and tremendous work of the many research teams which, over the years, contributed to the publication of more than 500 peer-review articles. We summarize the key points that were presented and discussed during this meeting.

Autoimmune Diseases↗

PubMed2002

Restricted specificity of intermolecular spreading to endogenous La (SS-B) and 60 kDa Ro (SS-A) in experimental autoimmunity.

Intermolecular spreading of humoral autoimmunity to different components of the Ro (SS-A) and La (SS-B) ribonucleoprotein (RNP) complex has been reported following immunization with a single component of the complex. Although the immune response to the immunizing antigen is polyclonal and diversified, little is known about the specificity of the recruited autoimmune responses to the endogenous Ro and La antigens which drive B-cell spreading. To determine the specificity of intermolecular spreading to La, we examined sera from 52 kDa Ro (Ro52)- and 60 kDa Ro (Ro60)-immunized C3H/HeJ mice for reactivity with recombinant fragments spanning endogenous mouse (m)La by enzyme-linked immunosorbent assay (ELISA) and immunoblotting. Sera from mice primed and boosted with recombinant Ro52 and Ro60 showed reactivity restricted to the COOH-terminal fragment of mLa (aa361-415). The recruited anti-La response was species-specific, cross-reacting weakly with the corresponding region on the human La molecule, and was abrogated by the preabsorption of the Ro-immune sera with mLa 361-415. Analogous experiments using recombinant mRo60 fragments spanning the mRo60 molecule revealed a similar pattern of oligoclonality in the specificity of anti-Ro60 autoimmunity following active immunization with La and Ro52. These results suggest that intermolecular-intrastructural T-B help is limiting in this model, and reveal unsuspected immunodominance of selected Ro-La epitopes in the spreading of the autoantibody response to these structures. The focusing of the recruited autoantibody response to these COOH-terminal regions of the Ro and La polypeptides may also reflect the surface accessibility of these regions in La-Ro RNP.

Animals↗

PubMed2001

Cognate T cell help is sufficient to trigger anti-nuclear autoantibodies in naive mice.

The mechanisms involved in the initiation of anti-nuclear autoantibodies are unknown. In this study, we show that one factor allowing anti-nuclear autoantibodies to develop is the incomplete nature of immune tolerance to many of these proteins. Immune responses in mice toward the ubiquitous nuclear autoantigen La/SS-B are much weaker than responses to the xenoantigen, human La (hLa; 74% identical). However, in transgenic (Tg) mice expressing hLa, the Ab response to this neo-autoantigen was reduced to a level resembling the weak autoimmune response to mouse LA: Partial tolerance to endogenous La autoantigen was restricted to the T compartment because transfer of CD4(+) T cells specific for one or more hLa determinants into mice bearing the hLa transgene was sufficient to elicit production of anti-hLa autoantibodies. Notably, only hLa- specific T cells from non-Tg mice, and not T cells from hLa Tg mice, induced autoantibody production in hLa Tg mice. These findings confirm partial Th tolerance to endogenous La and indicate the existence in normal animals of autoreactive B cells continuously presenting La nuclear AG: Therefore, the B cell compartment is constitutively set to respond to particular nuclear autoantigens, implicating limiting Th responses as a critical checkpoint in the development of anti-nuclear autoantibodies in normal individuals.

Adoptive Transfer↗

PubMed2001

Quantitative and qualitative influences of tapasin on the class I peptide repertoire.

Tapasin is critical for efficient loading and surface expression of most HLA class I molecules. The high level surface expression of HLA-B*2705 on tapasin-deficient 721.220 cells allowed the influence of this chaperone on peptide repertoire to be examined. Comparison of peptides bound to HLA-B*2705 expressed on tapasin-deficient and -proficient cells by mass spectrometry revealed an overall reduction in the recovery of B*2705-bound peptides isolated from tapasin-deficient cells despite similar yields of B27 heavy chain and beta(2)-microglobulin. This indicated that a proportion of suboptimal ligands were associated with B27, and they were lost during the purification process. Notwithstanding this failure to recover these suboptimal peptides, there was substantial overlap in the repertoire and biochemical properties of peptides recovered from B27 complexes derived from tapasin-positive and -negative cells. Although many peptides were preferentially or uniquely isolated from B*2705 in tapasin-positive cells, a number of species were preferentially recovered in the absence of tapasin, and some of these peptide ligands have been sequenced. In general, these ligands did not exhibit exceptional binding affinity, and we invoke an argument based on lumenal availability and affinity to explain their tapasin independence. The differential display of peptides in tapasin-negative and -positive cells was also apparent in the reactivity of peptide-sensitive alloreactive CTL raised against tapasin-positive and -negative targets, demonstrating the functional relevance of the biochemical observation of changes in peptide repertoire in the tapasin-deficient APC. Overall, the data reveal that tapasin quantitatively and qualitatively influences ligand selection by class I molecules.

Antigen Presentation↗

PubMed2001

Genomic diversity of natural killer cell receptor genes in three populations.

We report the distribution of genes encoding 11 killer cell immunoglobulin-like receptors (KIR) and 2 CD94:NKG2 receptors, in 32 Caucasians, 67 Australian Aborigines and 59 Vietnamese. The inhibitory and the activating KIR genes were found at different frequency in the three populations. No correlation was found between the polymorphism of the KIR genes and the HLA specificities of the tested samples. The most significant KIR associations were 2DL2 with 2DS2; 2DL2 with 2DS3 and 3DL1 with 2DS4 in all three study groups. In Caucasians and Vietnamese 2DS2 was associated with 2DS3 and 2DS1with 3DS1. KIR 2DL1 was strongly associated with three other KIRs: 2DL3, 3DL1 and 2DS4 in Aborigines. The distribution of the KIR phenotypes was different in the three populations. The AA1 phenotype was frequent in Vietnamese (42.4%) and Caucasians (31.2%), but very rare in Aborigines (1.5%). In contrast, the BB7 phenotype was very common for Aborigines (22.4%) and was absent in the two other groups. Our data demonstrate that different associations and putative KIR haplotypes could be distinguished in different populations.

Gene Frequency↗

PubMed2000

Tapasin-mediated retention and optimization of peptide ligands during the assembly of class I molecules.

The murine class I H-2Kb molecule achieves high level surface expression in tapasin-deficient 721.220 human cells. Compared with their behavior in wild-type cells, Kb molecules expressed on 721.220 cells are more receptive to exogenous peptide, undergo more rapid surface decay, and fail to form macromolecular peptide loading complexes. As a result, they are rapidly transported to the cell surface, reflecting a failure of endoplasmic reticulum retention mechanisms in the absence of loading complex formation. Despite the failure of Kb molecules to colocalize to the TAP and their rapid egress to the cell surface, Kb is still capable of presenting TAP-dependent peptides in the absence of tapasin. Furthermore, pool sequencing of peptides eluted from these molecules revealed strict conservation of their canonical H-2Kb-binding motif. There was a reduction in the total recovery of peptides associated with Kb molecules purified from the surface of tapasin-deficient cells. Comparison of the peptides bound to Kb in the presence and absence of tapasin revealed considerable overlap in peptide repertoire. These results indicate that in the absence of an interaction with tapasin, Kb molecules fail to assemble with calreticulin and TAP, yet they are still capable of acquiring a diverse array of peptides. However, a significant proportion of these peptides appear to be suboptimal, resulting in reduced cell surface stability of Kb complexes. Taken together, the findings indicate that tapasin plays an essential role in the formation of the class I loading complex, which retains class I heterodimers in the endoplasmic reticulum until optimal ligand selection is completed.

Animals↗

PubMed2000

Restricted polymorphism of the mannose-binding lectin gene of indigenous Australians.

Mannose-binding lectin (MBL) is an important complement-activating protein of the human innate immune system. Deficiency of MBL is associated with an increased risk of various infections and arises from three structural gene mutations in exon 1 (variants B, C and D) and/or the presence of a low efficiency promoter. The C allele is found in sub-Saharan Africa whereas the B allele is found elsewhere, suggesting that these mutations occurred after the suggested hominid migration out of Africa [100-150 000 years before present (BP)]. Paradoxically, these alleles may have a selective advantage in protection against intracellular pathogens and occur at particularly high frequencies in sub-Saharan Africa (C variant) and South America (B variant). Since hominids reached Australia at least 50 000 years ago, a study of MBL polymorphisms in the indigenous population was of interest. Using heteroduplex technology we found a paucity of MBL structural gene mutations in two population groups from geographically distinct regions. Of 293 individuals tested, 289 were wild-type and four were heterozygous for either the B or D allele. In each individual with an MBL mutation the HLA haplotype profile suggested some Caucasian admixture. We also found a restricted range of MBL promoter haplotypes and the serum MBL levels were higher than those of any other ethnic group studied to date (median 3.07 microg/ml). Our data suggest that the B mutation probably arose between 50 000 and 20 000 BP. Its absence from the founder gene pool of indigenous Australians may also partly explain their vulnerability to intracellular infections such as tuberculosis.

Alleles↗

PubMed2000

Distinct functions of tapasin revealed by polymorphism in MHC class I peptide loading.

Peptide assembly with class I molecules is orchestrated by multiple chaperones including tapasin, which bridges class I molecules with the TAP and is critical for efficient Ag presentation. In this paper, we show that, although constitutive levels of endogenous murine tapasin apparently are sufficient to form stable and long-lived complexes between the human HLA-B*4402 (B*4402) and mouse TAP proteins, this does not result in normal peptide loading and surface expression of B*4402 molecules on mouse APC. However, increased expression of murine tapasin, but not of the human TAP proteins, does restore normal cell surface expression of B*4402 and efficient presentation of viral Ags to CTL. High levels of soluble murine tapasin, which do not bridge TAP and class I molecules, still restore normal surface expression of B*4402 in the tapasin-deficient human cell line 721.220. These findings indicate distinct roles for tapasin in class I peptide loading. First, tapasin-mediated bridging of TAP-class I complexes, which despite being conserved across the human-mouse species barrier, is not necessarily sufficient for peptide loading. Second, tapasin mediates a function which probably involves stabilization of empty class I molecules and which is sensitive to structural compatibility of components within the loading complex. These discrete functions of tapasin predict limitations to the study of HLA molecules across some polymorphic and species barriers.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

Epitope mimics and determinant spreading: pathways to autoimmunity.

Infectious microorganisms have evolved molecules which mimic the host in order to aid in their undetected propagation. In response, mammalian hosts have evolved a highly diverse immune repertoire designed to eradicate rapidly changing pathogens. The generation of diversity in the immune repertoire results in potentially damaging self cross-reactivities which require multiple regulatory controls to keep autoreactive lymphocytes in check. Here, we review how molecular mimicry at the T cell level might be important in the development of systemic autoimmunity.

Animals↗

PubMed2000

Endogenous and exogenous factors contributing to the surface expression of HLA B27 on mutant APC.

We have examined the expression of HLA B*2705 in the mutant cell line 721.220, which lacks endogenous HLA A and B alleles and expresses a defective tapasin molecule. Several peptide sensitive mAbs distinguish between HLA B*2705 expressed on the surface of 721.220 cells (B27.220) and 721.220 cells co-transfected with human tapasin (B27.220.hTsn). This differential staining defines subtle differences in the conformation of HLA B27, which most likely reflect changes in the repertoire of antigenic peptides bound to B27 in the presence and absence of wild type tapasin. HLA B27 molecules expressed on the surface of 721.220 display increased levels of "free" B27 heavy chain (HC-10 staining), an epitope that is dependent on TAP-translocated peptides. The conformation and stability of B27 molecules was examined by investigating the integrity of mAb epitopes and the half-lives of these complexes on cells cultured with and without serum. The decay of surface B27 epitopes occurred more rapidly in B27.220 and this effect was exaggerated in serum free media. Importantly, the decay of surface B27 molecules in B27.220.hTsn cells was characterized by an early increase in HC-10 staining when the cells were grown in serum free media. This decay of B27 molecules via HC-10 reactive intermediates was not observed in B27.220 cells, implying molecules on these cells may already have passed through this stage prior to surface expression. Taken together these observations indicate that tapasin has a significant contribution to the composition and stability of the B27-bound peptide repertoire.

Antigen-Presenting Cells↗

PubMed2000

Genetic susceptibility and the link between cat exposure and rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic inflammatory disease for which immunogenetic susceptibility factors have been defined. In a recent case control study, it was shown that a prior intimate relationship with pet cats or budgerigars confers risk for subsequent development of RA after a period of latency. Pets are a potential reservoir for putative microbial agents that could be a stimulus for chronic inflammation subject to the influence of immunogenetic factors. Therefore, a study was undertaken to determine whether the presence of HLA-DRB1 alleles bearing the RA susceptibility motif influenced risk for RA associated with prior exposure to pets. METHODS: Blood samples were obtained from available RA patients and their case controls who had participated in the prior epidemiologic study. DR and DQ genotypes were determined by sequence analysis of oligonucleotides amplified from the DRB1 and DQB1 genes by polymerase chain reactions (PCR). Subjects were segregated according to pet exposure (as determined previously) and genotype for statistical analyses. RESULTS: The odds ratio (OR) for prepubertal exposure to cats and RA in available subjects irrespective of DRB1 genotype was 4.2 (CI, 2.1 to 8.5; P<.00002). The OR between prior exposure to cats and RA in subjects with the RA susceptibility genotype DRB1 *0401 and *0404 was 5.8 (CI, 1.4 to 26; P<.02) and >24 (CI, 1.6 to 813; P<.01), respectively. In subjects with the genotype DRB1 *1501, the association between RA and prior cat exposure was OR 8.4 (CI, 1.7 to 45; P<.01). No significant association between RA and pet exposure was found in patients selected according to other genotypes. The association between RA and the recognized HLA-DR susceptibility motif was slightly stronger in subjects with a history of intimate cat exposure (OR 4.7 [CI, 1.5 to 14.8], P<.005) than subjects without prior intimate exposure (OR 3.3 [CI; 1.2 to 9.3], P<.02). In the small number of subjects who had reported an intimate association with pet birds, no influence of DR genotype on risk for RA was discerned. CONCLUSIONS: Risk for RA associated with prior intimate exposure to cats is concentrated in subjects with the RA-susceptibility conferring genotypes DRB1 *0401 and *0404. The findings suggest an interaction between an environmen-tal agent associated with pet cats and certain RA susceptibility-conferring DR genotypes. The risk for RA associated with intimate cat exposure also was significant in subjects with DRB1*1501, a genotype not otherwise associated with RA, but which shares with known RA susceptibility-bearing alleles the presence of an electropositive pocket (Pocket 4) in the DR peptide binding groove.

Adult↗

PubMed2000

HLA-B27 expression and reactive arthritis susceptibility in two patient cohorts infected with Salmonella Typhimurium.

BACKGROUND: Reactive arthritis (ReA) is an inflammatory arthritis triggered by certain gastrointestinal and genitourinary infections. Single source outbreaks of triggering infections provide an opportunity to elucidate host susceptibility factors in this disease. AIM: To determine the role of Major Histocompatibility Complex (MHC) Class I alleles in ReA susceptibility after two large single source outbreaks of Salmonella Typhimurium gastroenteritis. METHODS: A questionnaire screening for features of ReA and a request for HLA class I typing were sent to all patients affected by two single source outbreaks of S. Typhimurium gastroenteritis. Individuals with arthritis of recent onset were interviewed, examined and diagnostic criteria for ReA applied. RESULTS: Nineteen cases of reactive arthritis, 11 female, were diagnosed in the 424 respondents with S. Typhimurium gastroenteritis from both outbreaks. Clinical features of the arthritis were similar to those described after other large single source outbreaks of Salmonella infection. HLA-B27 was expressed by only two of the 19 ReA patients and therefore did not predict susceptibility to this form of arthritis. Caucasians were, however, more likely to develop reactive arthritis than Asians. CONCLUSIONS: In this study, susceptibility to ReA was not increased in HLA-B27 positive individuals or males but was greater in those of Caucasian descent.

Adolescent↗

PubMed1999

Induction of autoimmunity by multivalent immunodominant and subdominant T cell determinants of La (SS-B).

We investigated the consequences of altering the form and valence of defined autodeterminants on the initiation and spreading of experimentally induced La/Ro autoimmunity. Anti-La and Ro (SS-A) Ab responses were monitored following immunization of healthy mice with defined immunodominant and subdominant T cell determinants of the La (SS-B) autoantigen synthesized as either monomeric or multiple antigenic (MAP) peptides. Abs to mouse La (mLa) developed faster and were of higher titer in mice immunized with the subdominant mLa25-44 MAP compared with mice immunized with the 25-44 monomer. Rapid intermolecular spreading of the autoimmune response to 60-kDa Ro was observed in AKR/J mice immunized with mLa25-44 MAP, but not in mice immunized repeatedly with monomeric peptide. A/J mice immunized and boosted with the known tolerogenic mLa287-301 determinant delivered as monomeric peptide failed to develop Abs to either intact mLa or mLa287-301 peptide. However, immunization with the multivalent mLa287-301 peptide led to the rapid production of high titer mLa autoantibodies associated with a proliferative T cell response to the mLa287-301 peptide. The data suggested that the enhanced immunogenicity of MAPs was not due to augmented Ag presentation or T cell stimulation. However, MAP-, but not monomer peptide-, containing immune complexes were potent substrates for Ab-dependent fixation of complement. These results demonstrate that the form of Ag responsible for inducing autoimmunity can profoundly influence the nature and magnitude of the immune response. Thus, molecular mimicry of tolerogenic and nontolerogenic self determinants might trigger autoimmunity under conditions of altered valence.

Amino Acid Sequence↗