Peggy L. Kendall, M.D.

Associate Professor
Faculty Appointments
Associate Professor of Medicine Associate Professor of Pathology, Microbiology and Immunology
M.D., Medicine, University of Texas Southwestern Medical School, Dallas, TexasB.S., Radio-TV-Film Communication, University of Texas, Austin, Texas
Office Address
T-3219 MCN
TN 2650
Research Description
The Kendall lab studies the role of B lymphocytes in Type 1 diabetes (T1D). Our long-term goal is to selectively block the survival and function of autoreactive B lymphocytes in this disease, while leaving normal cells available to fight infection. To do this, we study both autoreactive cellular activities in inflamed tissue, and B lymphocyte signaling events that allow the emergence and pathogenic function of autoreactive cells.

B lymphocytes promote T1D by acting as essential antigen-presenting cells to autoreactive T cells. Those T cells then mediate the destruction of pancreatic islets, resulting in loss of insulin-production, with downstream hyperglycemia and diabetes development. Inflamed pancreatic islets contain both T and B lymphocytes, organized into tertiary lymphoid structures (TLS). We use the nonobese diabetic (NOD) mouse to investigate the identity and function of these islet-invading B lymphocytes. We have discovered that B lymphocytes in diseased pancreas have a polyclonal repertoire overall, but are oligoclonal in each islet. The B cell repertoire is distinct from that in draining pancreatic lymph nodes, indicating a selective process in the inflamed tissue. The B cell receptors (BCRs) in these islets show evidence of somatic hypermutation (SHM), suggestive of T-B cellular interactions. We have also found that the B lymphocyte chemoattractant CXCL13 supports T-B cellular organization in the TLS. Surprisingly, TLS organization in this setting proves to be unnecessary for the selection of the B lymphocyte repertoire into the target tissue, for SHM of BCRs, or for diabetes development. Therefore, while TLS in nonimmune tissues appear morphologically similar to secondary lymphoid tissues, they may differ in important ways, including B lymphocyte antigenic selection, repertoire maturation, and the chemotactic factors underlying cellular recruitment and organization. Additional experiments have shown that autoreactive B cells infiltrate the islets, while nonautoreactive B cells do not, resulting in T-cell insulitis that does not cause diabetes. A future goal is to understand the factors that govern the trafficking and selection of these B lymphocytes into inflamed islets, and to develop methods of blocking islet infiltration.

A second line of investigation regards the contribution of B lymphocyte signaling to autoreactivity in T1D. Bruton’s tyrosine kinase (BTK) contributes to the propogation of signals from the BCR, leading to downstream calcium flux and nuclear translocation of transcription factors, including NFκB. BTK is a multidomained cytosolic tec kinase that serves as an adaptor, as well as a kinase, molecule. It is critical to B lymphocyte, but not T lymphocyte function. We have discovered that BTK supports T1D in the NOD model. Genetic depletion of BTK from NOD mice resulted in significant disease protection (83% healthy, vs. 31% of BTK-sufficient littermates), even though 90% of the B lymphocyte population in these mice survived. Disease-protection was abrogated by introduction of a transgenic anti-insulin BCR that forces the emergence of autoreactive B cells. We are now working to characterize the specific mechanisms underlying disease protection in this model, and to test the ability of specific BTK-inhibitors to prevent and reverse T1D.
Research Keywords
The role of B lymphocytes in type 1 diabetes.
Nyhoff LE, Barron BL, Johnson EM, Bonami RH, Maseda D, Fensterheim BA, Han W, Blackwell TS, Crofford LJ, Kendall PL. Bruton's Tyrosine Kinase Deficiency Inhibits Autoimmune Arthritis in Mice but Fails to Block Immune Complex-Mediated Inflammatory Arthritis. Arthritis & rheumatology (Hoboken, N.J.). 2016 Aug; 68(8): 1856-68. PMID: 26945549, DOI: 10.1002/art.39657, ISSN: 2326-5205.

Crofford LJ, Nyhoff LE, Sheehan JH, Kendall PL. The role of Bruton's tyrosine kinase in autoimmunity and implications for therapy. Expert Rev Clin Immunol [print-electronic]. 2016 Jul; 12(7): 763-73. PMID: 26864273, DOI: 10.1586/1744666X.2016.1152888, ISSN: 1744-8409.

Kendall PL. New Players in the Field of T1D: Anti-Peripherin B Lymphocytes. Diabetes. 2016 Jul; 65(7): 1794-6. PMID: 27329956, PMCID: PMC4915580, PII: 65/7/1794, DOI: 10.2337/dbi16-0017, ISSN: 1939-327X.

Hemler JA, Phillips EJ, Mallal SA, Kendall PL. The evolving story of human leukocyte antigen and the immunogenetics of peanut allergy. Ann. Allergy Asthma Immunol [print-electronic]. 2015 Dec; 115(6): 471-6. PMID: 26522257, PII: S1081-1206(15)00693-6, DOI: 10.1016/j.anai.2015.10.008, ISSN: 1534-4436.

Riley KG, Pasek RC, Maulis MF, Dunn JC, Bolus WR, Kendall PL, Hasty AH, Gannon M. Macrophages are essential for CTGF-mediated adult ß-cell proliferation after injury. Mol Metab. 2015 Aug; 4(8): 584-91. PMID: 26266091, PMCID: PMC4529497, PII: S2212-8778(15)00091-5, DOI: 10.1016/j.molmet.2015.05.002, ISSN: 2212-8778.

Case JB, Bonami RH, Nyhoff LE, Steinberg HE, Sullivan AM, Kendall PL. Bruton's Tyrosine Kinase Synergizes with Notch2 To Govern Marginal Zone B Cells in Nonobese Diabetic Mice. J. Immunol [print-electronic]. 2015 Jul 7/1/2015; 195(1): 61-70. PMID: 26034172, PMCID: PMC4551465, PII: jimmunol.1400803, DOI: 10.4049/jimmunol.1400803, ISSN: 1550-6606.

Bonami RH, Wolfle WT, Thomas JW, Kendall PL. NFATc2 (NFAT1) assists BCR-mediated anergy in anti-insulin B cells. Mol. Immunol [print-electronic]. 2014 Dec; 62(2): 321-8. PMID: 24507801, PMCID: PMC4125564, PII: S0161-5890(14)00012-1, DOI: 10.1016/j.molimm.2014.01.003, ISSN: 1872-9142.

Bonami RH, Sullivan AM, Case JB, Steinberg HE, Hoek KL, Khan WN, Kendall PL. Bruton's tyrosine kinase promotes persistence of mature anti-insulin B cells. J. Immunol [print-electronic]. 2014 Feb 2/15/2014; 192(4): 1459-70. PMID: 24453243, PMCID: PMC4083749, PII: jimmunol.1300125, DOI: 10.4049/jimmunol.1300125, ISSN: 1550-6606.

Zaynagetdinov R, Sherrill TP, Kendall PL, Segal BH, Weller KP, Tighe RM, Blackwell TS. Identification of myeloid cell subsets in murine lungs using flow cytometry. Am. J. Respir. Cell Mol. Biol. 2013 Aug; 49(2): 180-9. PMID: 23492192, PMCID: PMC3824033, PII: rcmb.2012-0366MA, DOI: 10.1165/rcmb.2012-0366MA, ISSN: 1535-4989.

Henry-Bonami RA, Williams JM, Rachakonda AB, Karamali M, Kendall PL, Thomas JW. B lymphocyte "original sin" in the bone marrow enhances islet autoreactivity in type 1 diabetes-prone nonobese diabetic mice. J. Immunol [print-electronic]. 2013 Jun 6/15/2013; 190(12): 5992-6003. PMID: 23677466, PMCID: PMC3679359, PII: jimmunol.1201359, DOI: 10.4049/jimmunol.1201359, ISSN: 1550-6606.

Kendall PL, Case JB, Sullivan AM, Holderness JS, Wells KS, Liu E, Thomas JW. Tolerant anti-insulin B cells are effective APCs. J. Immunol [print-electronic]. 2013 Mar 3/15/2013; 190(6): 2519-26. PMID: 23396943, PMCID: PMC3652276, PII: jimmunol.1202104, DOI: 10.4049/jimmunol.1202104, ISSN: 1550-6606.

Henry RA, Kendall PL, Thomas JW. Autoantigen-specific B-cell depletion overcomes failed immune tolerance in type 1 diabetes. Diabetes [print-electronic]. 2012 Aug; 61(8): 2037-44. PMID: 22698916, PMCID: PMC3402296, PII: db11-1746, DOI: 10.2337/db11-1746, ISSN: 1939-327X.

Henry RA, Kendall PL. CXCL13 blockade disrupts B lymphocyte organization in tertiary lymphoid structures without altering B cell receptor bias or preventing diabetes in nonobese diabetic mice. J. Immunol [print-electronic]. 2010 Aug 8/1/2010; 185(3): 1460-5. PMID: 20574003, PMCID: PMC3824617, PII: jimmunol.0903710, DOI: 10.4049/jimmunol.0903710, ISSN: 1550-6606.

Henry RA, Kendall PL, Woodward EJ, Hulbert C, Thomas JW. Vkappa polymorphisms in NOD mice are spread throughout the entire immunoglobulin kappa locus and are shared by other autoimmune strains. Immunogenetics [print-electronic]. 2010 Aug; 62(8): 507-20. PMID: 20556377, PMCID: PMC2970566, DOI: 10.1007/s00251-010-0457-9, ISSN: 1432-1211.

Moore DJ, Zienkiewicz J, Kendall PL, Liu D, Liu X, Veach RA, Collins RD, Hawiger J. In vivo islet protection by a nuclear import inhibitor in a mouse model of type 1 diabetes. PLoS ONE. 2010; 5(10): e13235. PMID: 20949090, PMCID: PMC2950856, DOI: 10.1371/journal.pone.0013235, ISSN: 1932-6203.

Kendall PL, Moore DJ, Hulbert C, Hoek KL, Khan WN, Thomas JW. Reduced diabetes in btk-deficient nonobese diabetic mice and restoration of diabetes with provision of an anti-insulin IgH chain transgene. J. Immunol [print-electronic]. 2009 Nov 11/15/2009; 183(10): 6403-12. PMID: 19841184, PMCID: PMC2970569, PII: jimmunol.0900367, DOI: 10.4049/jimmunol.0900367, ISSN: 1550-6606.

Boomershine CS, Chamberlain A, Kendall P, Afshar-Sharif AR, Huang H, Washington MK, Lawson WE, Thomas JW, Blackwell TS, Bhowmick NA. Autoimmune pancreatitis results from loss of TGFbeta signalling in S100A4-positive dendritic cells. Gut [print-electronic]. 2009 Sep; 58(9): 1267-74. PMID: 19625278, PMCID: PMC2719085, PII: gut.2008.170779, DOI: 10.1136/gut.2008.170779, ISSN: 1468-3288.

Kendall PL, Yu G, Woodward EJ, Thomas JW. Tertiary lymphoid structures in the pancreas promote selection of B lymphocytes in autoimmune diabetes. J. Immunol. 2007 May 5/1/2007; 178(9): 5643-51. PMID: 17442947, PII: 178/9/5643, ISSN: 0022-1767.

Kendall PL, Woodward EJ, Hulbert C, Thomas JW. Peritoneal B cells govern the outcome of diabetes in non-obese diabetic mice. Eur. J. Immunol. 2004 Sep; 34(9): 2387-95. PMID: 15307171, DOI: 10.1002/eji.200324744, ISSN: 0014-2980.

Thomas JW, Kendall PL, Mitchell HG. The natural autoantibody repertoire of nonobese diabetic mice is highly active. J. Immunol. 2002 Dec 12/1/2002; 169(11): 6617-24. PMID: 12444175, ISSN: 0022-1767.