Immunology
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Edmond J. Yunis

Pathology Department, Harvard Medical School
Dana Farber Cancer Institute
Dana Bldg., Room 740
44 Binney St
Boston, MA 02115
Tel: 617-632-3347
Fax: 617-632-4466
Email: edmond_yunis@dfci.harvard.edu

  

The main research focus of our laboratory is to establish the cellular, molecular, and genetic basis for the immunopathogenesis of susceptibility to develop active disease after Mycobaterium tuberculosis (Mtb) infection and AIDS after HIV-1 infection.

In the area of tuberculosis we have very interesting findings that were obtained in collaboration with Dr. Julio Granados from the National Institute of Immunology and Nutrition Salvador Zurbiran, Mexico and Dr. Harvey Cantor, Chief of the Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute. We have established an association of a genetic polymorphism in the distal region of MCP-1/CCL2 promoter (genotype GG) with susceptibility to develop clinical TB. We were able to describe that this susceptibility genotype was associated with highest levels of MCP-1/CCL2 in individuals with active pulmonary TB. Moreover, we observed that MCP-1/CCL2 inhibits IL-12 production in vitro by a mechanism involving the down-regulation of Osteopontin/Eta-1 receptor aVb3. These findings can potentially be used for the design of new therapeutic approaches to treat pulmonary TB. Also, we have established associations of polymorphisms in the CC16 and RXRb genes with resistance to develop active TB, and HLA-DQB1 alleles encoding Asp in position 57 with susceptibility to disease progression.

In the area of HIV-1 infection and progression to AIDS, we have established an association homozygosity of HLA-B alleles of the HLA-Bw4 public specificity and HLA-B44 alleles with control of HIV viremia and protection from AIDS exists. We are currently in search for the mechanisms of protection. We know that the HLA-B locus is located close to the MICA and MICB loci (encoding the ligands of NKG2D receptors) and that some HLA-B alleles can be inherited in linkage disequilibrium with alleles of these genes.

Protection from AIDS may also have something to do with the fact that almost all HLA-B alleles of the Bw4 specificity and some of the Bw6 specificity encode leader peptides that when digested in the proteasome generate nona-peptides that interfere with the folding and expression of HLA-E molecules. This may hamper the delivery of inhibitory signals through the HLA-E/CD94-NKG2A pathway to NK and some CD8+ T cells in almost all individuals carrying Bw4 alleles and some carrying Bw6 alleles, resulting in killing of HIV infected cells and protection from developing AIDS. Also, four alleles have been identified in the HLA-E loci and the ability of the encoded molecules to fold with HLA Class-I derived peptides and associations of these alleles with progression to AIDS is unknown. We are currently searching for these answers.

Oxidized clozapine induces apoptosis of neutrophils in culture. Increased apoptosis was associated with downregulation of CD16 gene as well as increased FasL gene expression in PMN cells. Our results suggest a direct role of oxidized clozapine metabolite in inducing apoptosis via Fas-FasL ligand interaction and suggest possible intervention of such drug induced blood dyscrasias.

 

Papers & Publications:

  1. Alper CA, Marcus-Bagley D, Awdeh Z, Kruskall MS, Eisenbarth GS, Brink SJ, Katz AJ, Stein R, Bing DH, Yunis EJ, Schur PH. Prospective analysis suggests susceptibility genes for deficiencies of IgA and several other immunoglobulins on the [HLA-B8, SC01, DR3] conserved extended haplotype. Tissue Antigens. 2000 Sep;56(3):207-16.
  2. Salazar M, Varela A, Ramirez LA, Uribe O, Vasquez G, Egea E, Yunis EJ, Iglesias-Gamarra A. Association of HLA-DRB1*1602 and DRB1*1001 with Takayasu arteritis in Colombian mestizos as markers of Amerindian ancestry. Int J Cardiol. 2000 Aug 31;75 Suppl 1:S113-6.
  3. Alper CA, Dubey DP, Yunis EJ, Awdeh Z. A simple estimate of the general population frequency of the MHC susceptibility gene for autoimmune polygenic disease. Exp Clin Immunogenet. 2000;17(3):138-47.
  4. Leung JY, McKenzie FE, Uglialoro AM, Flores-Villanueva PO, Sorkin BC, Yunis EJ, Hartl DL, Goldfeld AE. Identification of phylogenetic footprints in primate tumor necrosis factor-alpha promoters. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6614-8.
  5. Larsen CE, Xu J, Lee S, Dubey DP, Uko G, Yunis EJ, Alper CA. Complex cytokine responses to hepatitis B surface antigen and tetanus toxoid in responders, nonresponders and subjects naive to hepatitis B surface antigen. Vaccine. 2000 Jul 1;18(26):3021-30.
  6. Boussiotis VA, Tsai EY, Yunis EJ, Thim S, Delgado JC, Dascher CC, Berezovskaya A, Rousset D, Reynes JM, Goldfeld AE. IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. J Clin Invest. 2000 May;105(9):1317-25.
  7. Hurley CK, Baxter-Lowe LA, Begovich AB, Fernandez-Vina M, Noreen H, Schmeckpeper B, Awdeh Z, Chopek M, Salazar M, Williams TM, Yunis EJ, Kitajima D, Shipp K, Splett J, Winden T, Kollman C, Johnson D, Ng J, Hartzman RJ, Hegland J. The extent of HLA class II allele level disparity in unrelated bone marrow transplantation: analysis of 1259 National Marrow Donor Program donor-recipient pairs. Bone Marrow Transplant. 2000 Feb;25(4):385-93.
  8. Dubey DP, Husain Z, Levitan E, Zurakowski D, Mirza N, Younes S, Coronell C, Yunis D, Yunis EJ. The MHC influences NK and NKT cell functions associated with immune abnormalities and lifespan. Mech Ageing Dev. 2000 Feb 7;113(2):117-34.
  9. Flores-Villanueva P.O., Yunis EJ, Delgado JC, Vittinghoff E, Buchbinder S, Leung JY, Uglialoro AM, Clavijo OP, Rosenberg ES, Kalams SA, Braun JD, Boswell SL, Walker BD, Goldfeld AE. Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity. Proc Natl Acad Sci U S A. 2001 Apr 24; 98:5140-5145.
  10. Novitsky V, Flores-Villanueva PO, Chigwedere P, Gaolekwe S, Bussman H, Sebetso G, Marlink R, Yunis EJ, Essex M. Identification of most frequent HLA class I antigen specificities in Botswana: relevance for HIV vaccine design. Hum Immunol. 2001 Feb;62(2):146-56.
  11. Husain Z, Delgado J, Pinto C, Yunis E : Increased FasL expression correlates with apoptotic changes in granulocytes cultured with oxidized clozapine. Submitted.
  12. Flores-Villaueva P.O., Granados J., Dobesova L.M., Baker J.M., Zuniga J., Selman M. and Yunis E.J.. Influence of a MCP-1 promoter Polymorphism with plasma levels of MCP-1 and progression to clinical tuberculosis. Submitted.
  13. Flores-Villaueva P.O., Yunis E.J., Dobesova L.M., Selman M. and Granados J. A CC16 gene variant is associated with Mycobacterium tuberculosis latent infection. Submitted.
  14. Flores-Villaueva P.O., Yunis E.J., Dobesova L.M., Selman M. and Granados J. A RXRb gene polymorphism is associated with resistance to develop active tuberculosis after Mycobacterium tuberculosis infection. In preparation.