Professor/Director, Division of Pediatric Rheumatology
Director, Pediatric Rheumatology Fellowship Program



Children's of Alabama (CoA)
Department of Pediatrics, Division of Rheumatology
Children's Park Place North , Suite G10
Birmingham, AL 35233

Telephone: 205-638-9438
FAX: (205) 996-9545

Administrative Assistant: Kim Jenkins
Telephone: (205) 638-6466

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


Research Description

CD154 (CD40 ligand) dysregulation in lupus.  Systemic lupus erythematosus, the prototypic autoimmune disorder, affects 1 in 2,000 women in the United States. CD154HSS . 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 TFregulateCD154 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 NFATbindHIV 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 Figure

Genes and Immunity (2012) 13: 289-298.


Potential projects for trainees

  • Exploration of the functional impact of patient derived HLH mutations on the lymphocyte cytolytic pathway
  • Defining the role of CD4 T cell transcription factors during HIV-1 infection and latency



Click here for a complete list of publications on PubMed. Below are a few selected papers.

Ravelli A, Minoia F, Davì S, Horne A, Bovis F, Pistorio A, Aricò M, Avcin T, Behrens EM, De Benedetti F, Filipovic L, Grom AA, Henter JI, Ilowite NT, Jordan MB, Khubchandani R, Kitoh T, Lehmberg K, Lovell DJ, Miettunen P, Nichols KE, Ozen S, Pachlopnik Schmid J, Ramanan AV, Russo R, Schneider R, Sterba G, Uziel Y, Wallace C, Wouters C, Wulffraat N, Demirkaya E, Brunner HI, Martini A, Ruperto N, Cron RQ; Paediatric Rheumatology International Trials Organisation; Childhood Arthritis and Rheumatology Research Alliance; Pediatric Rheumatology Collaborative Study Group; Histiocyte Society. 2016. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Arthritis Rheumatol. 2016(3):566-76. PMID: 26314788

Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, Cron RQ, Opal SM. 2016. Interleukin-1 Receptor Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial. Crit Care Med. 2016(2):275-81. PMID: 26584195; PMC5378312

Zhang M, Bracaglia C, Prencipe G, Bemrich-Stolz CJ, Beukelman T, Dimmitt RA, Chatham WW, Zhang K, Li H, Walter MR, De Benedetti F, Grom AA, Cron RQ. 2016. A Heterozygous RAB27A Mutation Associated with Delayed Cytolytic Granule Polarization and Hemophagocytic Lymphohistiocytosis. J Immunol. 196(6):2492-503. PMID: 26880764   PMC4779709

Schulert GS, Zhang M, Fall N, Husami A, Kissell D, Hanosh A, Zhang K, Davis K, Jentzen JM, Napolitano L, Siddiqui J, Smith LB, Harms PW, Grom AA, Cron RQ. 2016. Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza. J Infect Dis. 213(7):1180-8. PMID: 26597256;  PMC4779301

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; PMC3436993  (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.)



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