<i>H2E</i>-Derived Eα52-68 Peptide Presented by H2Ab Interferes with Clonal Deletion of Autoreactive T Cells in Autoimmune Thyroiditis

Brown, Nicholas K.; McCormick, Daniel J.; David, Chella S.; Kong, Yi

doi:10.4049/jimmunol.180.10.7039

Cited by 6 publications

(12 citation statements)

References 42 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Though the majority of reports have demonstrated a protective role for I-E in a number of autoimmune models, a thorough study on autoimmune thyroiditis showed increased susceptibility imparted by I-E expression (Brown et al, 2008; Christadoss et al, 1990; Gonzalez-Gay et al, 1994; Lund et al, 1990; Merino et al, 1993; Nishimoto et al, 1987; Reich et al, 1989). Our study provides a unique opportunity to relate the impact of I-E on autoimmunity to its effects on other types of immune responses, a comparison that has not been done before.…”

Section: Resultsmentioning

confidence: 99%

“…As the peptide is capable of occupying approximately 10-15% of all I-A b molecules (Brown et al, 2008; Rudensky et al, 1991), it can prevent the selection of certain I-A b -restricted cells in the thymus or compete with the presentation of pathogenic peptides in the periphery. The Eα peptide along with the I-E b MHC could both contribute to the altered T cell repertoire and T cell responses in the B6.E + mice.…”

Section: Discussionmentioning

confidence: 99%

“…Expression of I-E on other backgrounds including H-2 b and H-2 q likewise resulted in protection from lupus, experimental autoimmune myasthenia gravis, and collagen-induced arthritis (Christadoss et al, 1990; Gonzalez-Gay et al, 1994; Merino et al, 1993). Yet there is a report that the addition of I-E b actually resulted in detrimental effects, enhancing susceptibility to disease in autoimmune thyroiditis (Brown et al, 2008). Having negative effects from the addition of a second MHC was also corroborated in a different model (viral infection) with a different MHC being investigated (I-A).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Both positive and negative effects on immune responses by expression of a second class II MHC molecule

Wang

Allen

2014

Molecular Immunology

View full text Add to dashboard Cite

It is perplexing why vertebrates express a limited number of Major Histocompatibility Complex (MHC) molecules when theoretically, having a greater repertoire of MHC molecules would increase the number of epitopes presented, thereby enhancing thymic selection and T cell response to pathogens. It is possible that any positive effects would either be neutralized or outweighed by negative selection restricting the T cell repertoire. We hypothesize that the limit on MHC number is due to negative consequences arising from expressing additional MHC. We compared T cell responses between B6 mice (I-A+) and B6.E+ mice (I-A+, I-E+), the latter expressing a second class II MHC molecule, I-Eb, due to a monomorphic Eαk transgene that pairs with the endogenous I-Eβb chain. First, the naive T cell Vβ repertoire was altered in B6.E+ thymi and spleens, potentially mediating different outcomes in T cell reactivity. Although the B6 and B6.E+ responses to hen egg-white lysozyme (HEL) protein immunization remained similar, other immune models yielded differences. For viral infection, the quality of the T cell response was subtly altered, with diminished production of certain cytokines by B6.E+ CD4+ T cells. In alloreactivity, the B6.E+ T cell response was significantly dampened. Finally, we observed markedly enhanced susceptibility to experimental autoimmune encephalomyelitis (EAE) in B6.E+ mice. This correlated with decreased percentages of nTreg cells, supporting the concept of Tregs exhibiting differential susceptibility to negative selection. Altogether, our data suggest that expressing an additional class II MHC can produce diverse effects, with more severe autoimmunity providing a compelling explanation for limiting the expression of MHC molecules.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Both positive and negative effects on immune responses by expression of a second class II MHC molecule

Wang

Allen

2014

Molecular Immunology

View full text Add to dashboard Cite

show abstract

“…Three human α5-integrin peptides comprising residues 637–649 (DKAQILLDCGEDN), 642–649 (LLDCGEDN), and 710–735 (PGNFSSLSCDYFAVNQSRLLVCDLGN); and sEGFR 31-mer peptide comprising residues 604–634 (PGNESLKAMLFCLFKLSSCNQSNDGSVSHQS) were synthesized by the Peptide Synthesis Facility of Mayo Clinic (Rochester, MN) using orthogonal solid phase methods on RINK amide resin (EMD Chemicals/Novabiochem, Gibbstown, NJ) as described previously (16). Briefly, peptides linked to RINK resin were assembled on a Liberty Microwave Peptide Synthesizer (0.1 mmol, CEM Corp., Matthews, NC) or APEX 396 Multiple Peptide Synthesizer (0.04 mmol, AAPPTEC, Louisville, KY) using Nα-9-fluorenyl-methoxycarbonyl protected L-amino acids and synthesis protocols provided by each instrument’s manufacturer.…”

Section: Methodsmentioning

confidence: 99%

Identification of Immunoreactive Regions of Homology between Soluble Epidermal Growth Factor Receptor and α5-Integrin

et al. 2011

Self Cite

View full text Add to dashboard Cite

Proteins encoded by the epidermal growth factor receptor (EGFR/HER1/ERBB1) gene are being studied as diagnostic, prognostic, and theragnostic biomarkers for numerous human cancers. The clinical application of these tissue/tumor biomarkers has been limited, in part, by discordant results observed for EGFR expression using different immunological reagents. Previous studies have used EGFR-directed antibodies that cannot distinguish between full-length vs. soluble EGFR (sEGFR) expression. We have generated and characterized an anti-sEGFR polyclonal antiserum directed against a 31-mer peptide (residues 604–634) located within the unique 78 amino acid carboxy-terminal sequence of sEGFR. Here, we use this antibody to demonstrate that sEGFR is co-expressed with EGFR in a number of carcinoma-derived cell lines. In addition, we show that a second protein of ~140-kDa (p140) also is detected by this antibody. Rigorous biochemical characterization identifies this second protein to be α5-integrin. We show that a 26 amino acid peptide in the calf domain of α5-integrin (residues 710–35) shares 35% sequence identity with a 31-mer carboxy-terminal sEGFR peptide, and exhibits approximately 5 times lower affinity for anti-sEGFR than does the homologous 31-mer sEGFR peptide. We conclude that the carboxy-terminus of sEGFR and the calf-1 domain of α5-integrin share a region of sequence identity, which results in their mutual immunological reactivity with anti-sEGFR. We also demonstrate that anti-sEGFR promotes 3D tissue cohesion and compaction in vitro, further suggesting a functional link between sEGFR and α5-integrin and a role of the calf-1 domain in cell adhesion. These results have implications for the study of both EGFR and sEGFR as cancer biomarkers, and also provide new insight into the mechanisms of interaction between cell surface EGFR isoforms and integrin in complex processes such as cell adhesion and survival signaling.

show abstract

“…We delineated five mTg peptides that bind to H2A b and are immunogenic for A + E − and A + E + mice [53]. One of these H2A-restricted peptides, mTg1677, is pathogenic for A + E + mice and Treg-depleted A + E − mice [53], mirroring intact mTg [23]. Likewise, we found responses to H2E-restricted peptides to be higher in both A − E + and A + E + mice after in vivo depletion of Tregs [46].…”

Section: Possible Reciprocal Role Of Tregs In the Suppressive Effementioning

confidence: 99%

Autoimmune thyroiditis: A model uniquely suited to probe regulatory T cell function

Kong

Morris

Brown

et al. 2009

Journal of Autoimmunity

Self Cite

View full text Add to dashboard Cite

Murine experimental autoimmune thyroiditis (EAT) is a model for Hashimoto’s thyroiditis that has served as a prototype of T cell-mediated autoimmunity for more than three decades. Key roles for MHC restriction and autoantigen influence on susceptibility to autoimmunity have been demonstrated in EAT. Moreover, it has served a unique role in investigations of self tolerance. In the early 1980s, self tolerance and resistance to EAT induction could be enhanced by increasing circulating levels of the autoantigen, thyroglobulin (Tg), by exogenous addition as well as endogenous release. This observation, directly linking circulating self antigen to self tolerance, led to subsequent investigations of the role of regulatory T cells (Tregs) in self tolerance. These studies revealed that protection against autoimmunity, in both naive and tolerized mice, was mediated by thymically-derived CD4+CD25+Foxp3+ Tregs. Moreover, these naturally-existing Tregs required proper costimulation, in context with autoantigen presentation, to maintain and enhance self tolerance. In particular was the selected use of MHC- and heterologous Tg-restricted models from both conventional and transgenic mice. These models helped to elucidate the complex interplay between autoantigen presentation and MHC class II-mediated T cell selection in the development of Treg and autoreactive T cell repertoires determining susceptibility to autoimmunity. Here we describe these investigations in further detail, providing a context for how EAT has helped shape our understanding of self tolerance and autoimmunity.

show abstract

H2E-Derived Eα52-68 Peptide Presented by H2Ab Interferes with Clonal Deletion of Autoreactive T Cells in Autoimmune Thyroiditis

Cited by 6 publications

References 42 publications

Both positive and negative effects on immune responses by expression of a second class II MHC molecule

Both positive and negative effects on immune responses by expression of a second class II MHC molecule

Identification of Immunoreactive Regions of Homology between Soluble Epidermal Growth Factor Receptor and α5-Integrin

Autoimmune thyroiditis: A model uniquely suited to probe regulatory T cell function

Contact Info

Product

Resources

About