Professor/Director, Division of Pediatric Rheumatology
Director, Pediatric Rheumatology Fellowship Program
Children's of Alabama (CoA)
Department of Pediatrics, Division of Rheumatology
1601 4th Avenue South, Suite 210
Birmingham, AL 35233
FAX: (205) 996-9545
Administrative Assistant: Wendy Baker
Telephone: (205) 996-9191
For a detailed CV, please click here
B.S. (Biomedical Sciences), University of California, Riverside, CA, 1985
Pre-doctoral fellow (Howard Hughes Medical Institute), National Institutes of Health, Bethesda, MD, 1986-1987
Ph.D. (Immunology), University of Chicago, Chicago, IL, 1990
M.D., UCLA, Los Angeles, CA, 1991
Residency (Pediatrics), Stanford Children's Hospital, Palo Alto, CA, 1991-1994
Fellowship (Pediatric Rheumatology), University of Washington, Seattle, WA, 1994-1997
Post-doctoral Fellow (Howard Hughes Medical Institute), Stanford University, Palo Alto, CA, 1997-1999
CD154 (CD40 ligand) dysregulation in lupus. Systemic lupus erythematosus, the prototypic autoimmune disorder, affects 1 in 2,000 women in the United States. . Although the etiology and pathogenesis are unclear, the over-expression of the TNF family member, CD154, on CD4 T lymphocytes clearly contributes to disease pathology, both in mouse models and in humans with disease. Our ultimate goal is to identify cis- and trans-acting elements that contribute to the dysregulated expression of CD154 in SLE and other autoimmune disorders. We initially characterized the human CD154 transcriptional promoter and demonstrated its cyclosporin A (CsA) sensitivity. We are currently probing the hCD154 gene locus by DNase I hypersensitive site mapping to identify novel regulatory elements. We have identified and partially characterized a 5' transcriptional enhancer, a 3' transcriptional enhancer, and a 3' untranslated mRNA stability element. In addition, we have identified an uncharacterized 5' hypersensitive site farther upstream of the transcription start site. We are currently exploring the activities of these various CD154 regulatory elements as transgenes in a mouse model of SLE. In conjunction, we have identified various transcription factors and RNA binding proteins, which had not been previously described to regulate CD154 expression. We are currently exploring these factors and epigenetic modulations of the locus for their contributions to CD154 dysregulation in SLE.
Host transcription factors exploited by HIV-1. HIV-1, the cause of AIDS, has infected over 40 million individuals world-wide. Although vast improvements in therapy have been developed over the last decade, HIV-1 cannot be totally eliminated from the host due to its ability to enter a resting or latent state in CD4 T cells. Because HIV-1 relies on host transcription factors to replicate, we are exploring the role of the calcium activated nuclear factor of activated T cells (NFAT) transcription factors in regulating HIV-1 transcription. We and others have shown that the CsA-sensitive NFAT proteins bind to the proximal HIV-1 promoter/long terminal repeat (LTR) in vitro and up-regulate HIV-1 transcription. We have further demonstrated that NFAT proteins bind to the integrated HIV-1 LTR in primary human CD4 T cells in vivo by chromatin immunoprecipitation, and this binding is disrupted by the regulatory T cell transcription factor, FOXP3. In addition, we are attempting to exploit NFAT activation as a means of activating HIV-1 LTR activity in latently infected cells. Recently, we identified a novel binding site for the c-maf transcription factor located adjacent to the proximal NFAT sites in the HIV-1 LTR. Our studies reveal synergistic transcriptional activation and increased infection of HIV-1 by c-maf, NFAT2, and NFkB in primary human IL-4-producing CD4 T cells. Thus, c-maf will likely be a novel therapeutic target in the treatment of HIV-1. In addition, we are exploring the inhibition of HIV-1 transcription in FoxP3-expressing regulatory T cells (Tregs), as well as the ability of these cells to inhibit HIV-1 expression in neighboring non-Treg CD4 T cells and polarized macrophage populations.
Mutations in hemophagocytic lymphohistioctyosis (HLH) genes contributing to macrophage activation syndrome (MAS). Familial HLH is a fatal group of rare (1 in 50,000 live births) autosomal recessive disorders presenting in infancy. The biallelic mutations in the various HLH genes (e.g. perforin) results in the inability of CD8 T cells and natural killer (NK) cells to lyse target cells though the perforin-dependent cytolytic pathway. This leads to prolonged engagement of the lytic cell and its antigen-presenting target cell, giving rise to a massive pro-inflammatory cytokine storm. The cytokine storms results in pancytopenia, coagulopathy, liver and central nervous system dysfunction, and eventual multi-organ failure. MAS, or secondary HLH, is a similar frequently fatal condition seen as a complication of a variety of infectious (e.g. EBV), oncologic (e.g. T cell leukemia), and rheumatic disorders (e.g. systemic lupus erythematosus). Recently, monoallelic mutations in classic familial HLH genes (e.g. PRF1, MUNC13-4, MUNC18-2, RAB27A, STX11) have been identified in a substantial subset of patients with late onset HLH/MAS. Our lab is studying the effect of these patient derived single copy HLH gene mutations on NK cell cytolytic activity. We are further exploring how these mutations disrupt interactions with other proteins involved in the cytolytic pathway via a variety of cellular, biochemical, cell biological, and imaging technologies. This work underscores the importance of these relatively common monoallelic mutations in contributing to secondary HLH/MAS, via dominant negative or hypomorphic effects, among a large segment of the general population.
Genes and Immunity (2012) 13: 289-298.
Potential projects for trainees
Click here for a complete list of publications on PubMed. Below are a few selected papers.
Duverger, A., Jones, J., May, J., Bibollet-Rusch, F., Wagner, F.A., Cron, R.Q., and Kutsch, O. 2009. Determinants of HIV-1 latency establishment. J. Virol. 83:3078-3093. PMID: 19144703
Torgerson, T.R., Genin, A., Chen, C., Zhang, M., Zhou, B., Anover, S., Frank, M.B., Dozmorov, I., Ocheltree, E., Kulmala, E., Centola, M., Ochs, H.D., Wells, A.D., and Cron, R.Q. 2009. FOXP3 inhibits activation-induced NFAT2 expression in T cells thereby limiting effector cytokine expression. J. Immunol. 183:907-915. PMID: 19564342
Mehta, J., Genin, A., Brunner, M., Scalzi, L.V., Mishra, N., Beukelman, T., and Cron, R.Q. 2010. Prolonged expression of CD154 on CD4 T cells from pediatric lupus patients correlates with increased CD154 transcription, increased nuclear factor of activated T cell activity, and glomerulonephritis. Arthritis Rheum. 62: 2499-2509. PMID: 20506525
Miettunen PM, Narendran A, Jayanthan A, Behrens EM, Cron RQ. 2010. Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients. Rheumatology (Oxford). 50(2):417-9. PMID: 20693540
Nigrovic PA, Mannion M, Prince FH, Zeft A, Rabinovich CE, van Rossum MA, Cortis E, Pardeo M, Miettunen PM, Janow G, Birmingham J, Eggebeen A, Janssen E, Shulman AI, Son MB, Hong S, Jones K, Ilowite NT, Cron RQ, Higgins GC. 2011. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum. 63(2):545-55. PMID: 21280009
Zhang M, Clausell A, Robinson T, Yin J, Chen E, Johnson L, Weiss G, Sabbaj S, Lowe RM, Wagner FH, Goepfert PA, Kutsch O, Cron RQ. 2012. Host Factor Transcriptional Regulation Contributes to Preferential Expression of HIV Type 1 in IL-4-Producing CD4 T Cells. J Immunol. 189(6): 2746-2757. PMID: 22875803 (This article was featured in the "In This Issue" section of the Journal of Immunology, which highlights articles that are among the top 10% of articles published in the journal.)
Ravelli A, Grom AA, Behrens EM, Cron RQ. 2012. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun. 13(4):289-298. PMID: 22418018
Duverger A, Wolschendorf F, Zhang M, Wagner F, Hatcher B, Jones J, Cron RQ, van der Sluis RM, Jeeninga RE, Berkhout B, Kutsch O. 2013. An AP-1 binding site in the enhancer/core element of the HIV-1 promoter controls the ability of HIV-1 to establish latent infection. J Virol. 87(4):2264-2277. PMID: 23236059 PMCID: PMC3571467
Harms AS, Cao S, Rowse AL, Thome AD, Li X, Mangieri LR, Cron RQ, Shacka JJ, Raman C, Standaert DG. 2013. MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J Neurosci. 33(23):9592-9600. PMID: 23739956 PMCID: PMC3903980
Duverger A, Wolschendorf F, Anderson JC, Wagner F, Bosque A, Shishido T, Jones J, Planelles V, Willey C, Cron RQ, Kutsch O. 2014. Kinase control of latent HIV-1 infection: PIM-1 kinase as a major contributor to HIV-1 reactivation. J Virol. 88(1):364-376. PMID: 24155393 PMCID: PMC3911731
Lowe RM, Genin A, Orgun N, Cron RQ. 2014. IL-15 prolongs CD154 expression on human CD4 T cells via STAT5 binding to the CD154 transcriptional promoter. Genes Immun. 15(3):137-144. PMID: 24500400 PMCID: PMC4133980
Zhang M, Ma Z, Selliah N, Weiss G, Genin A, Finkel TH, Cron RQ. 2014. The impact of Nucleofection® on the activation state of primary human CD4 T cells. J Immunol Methods. 408:123-131. PMID: 24910411 PMCID: 4120863
Zhang M, Behrens EM, Atkinson TP, Shakoory B, Grom AA, Cron RQ. 2014. Genetic defects in cytolysis in macrophage activation syndrome. Curr Rheumatol Rep. 16(9):439-447. PMID: 25086802
Stoll ML, Kumar R, Morrow CD, Lefkowitz EJ, Cui X, Genin A, Cron RQ, Elson CO. 2014. Altered microbiota associated with abnormal humoral immune responses to commensal organisms in enthesitis-related arthritis. Arthritis Res Ther. 16(6):486-497. PMID: 25434931 PMCID: PMC4272554