The Enders Group - Models of human primary immunodeficiencies

Normal lymphocyte development and function is essential for protection against recurrent infections. Genetic defects in either the development or function of lymphocytes can cause a group of diseases called human primary immunodeficiencies (PIDs). The mutations found in the rare patients with PID often highlight crucial, non-redundant steps in the development or function of the immune system, therefore, it is important to understand the genetic and molecular mechanisms underlying PIDs.

Despite great progress in this area, particularly in the last few years, there are still patients with PIDs without a molecular diagnosis. As part of the Centre for Personalised Immunology (CPI), an NHMRC funded Centre for Research Excellence, we are attempting to change this. In cooperation with clinicians and researchers from Australia and overseas, we are sequencing the genome of patients with unexplained PIDs. This work has led to the discovery of likely causal mutations in genes not previously associated with immune defects. To follow up on these mutations we have generated matching mouse models through CRISPR/Cas9 genome editing and are now analysing these to better understand disease pathogenesis in patients.

A particular focus of our group are defects in the regulation of the cytoskeleton and how these contribute to a PID called Hyper IgE syndrome (HIGE). For the last few years we have known that defects in the upstream regulator DOCK8 can underlie HIGE. More recently, it was found that mutations in the actin regulator ARPC1B can also cause a similar phenotype. In addition to immunodeficiency, some patients with ARPC1B deficiency also present with bleeding defects. But what causes these differences, both clinically and on a cellular level, is not understood.

We are currently recruiting a postdoctoral fellow to work on this project.

We are also investigating a range of other mutant mouse strains with defects in B cell development and survival. Examples of this line of research are the discoveries that flipping of phospholipids across the cell membrane is essential for the normal development of B cells in the bone marrow (Yabas et al, Nature Immunology 12:441-449, 2011) and an essential role for the intramembrane endopeptidase SPPL2A for survival and function of mature B cells and CD8- dendritic cells (Bergmann et al, The Journal of experimental medicine 210:31-40, 2013). In collaboration with Stefan Broer from the Research School of Biology at ANU, we have also recently started analysing how defects in amino acid homeostasis affects B cell responses.

We have opportunities for honours and post-graduate projects in both these areas. Please contact Anselm by email to obtain further information.

Publications

  1. Yabas, M, Coupland, LA, Cromer, D, Winterberg, M, Teoh, NC, D'Rozario, J, Kirk, K, Bröer, S, Parish, CR and Enders, A., 2014, Mice deficient in the putative phospholipid flippase ATP11C exhibit altered erythrocyte shape, anemia, and reduced erythrocyte life span. Journal of Biological Chemistry 289(28):19531–7.
     
  2. Enders, A, Short, A, Miosge, LA, Bergmann, H, Sontani, Y, Bertram, EM, Whittle, B, Balakishnan, B, Yoshida, K, Sjollema, G, Field, MA, Andrews, TD, Hagiwara, H and Goodnow, CC., 2014, Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively spliced Igh product made by mature B lymphocytes. Proc Natl Acad Sci USA 111(12):4513-4518.
     
  3. Crawford, G*, Enders, A*, Gileadi, U* (*Equal contribution), Stankovic, S, Zhang, Q, Lambe, T, Crockford, TL, Lockstone, HE, Freeman, A, Arkwright, PD, Smart, JM, Ma, CS, Tangye, SG, Goodnow, CC, Cerundolo, V, Godfrey, DI, Su, HC, Randall, KL and Cornall, RJ., 2013, DOCK8 is critical for the survival and function of NKT cells. Blood 122(12):2052–61. r 10.
     
  4. Teh, CE, Horikawa, K, Arnold, CN, Beutler, B, Kucharska, EM, Vinuesa, CG, Bertram, EM, Goodnow, CC and Enders, A., 2013, Heterozygous mis-sense mutations in Prkcb as a critical determinant of anti-polysaccharide antibody formation. Genes and Immunity 14:223-33.
     
  5. Stepensky, P, Keller, B, Buchta, M, Kienzler, AK, Elpeleg, O, Somech, R, Cohen, S, Shachar, I, Miosge, LA, Schlesier, M,  Fuchs, I, Enders, A, Eibel, H, Grimbacher, B  and Warnatz, K., 2013, Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects. The Journal of allergy and clinical immunology 131:477-485.  
                   
  6. Bergmann, H, Yabas, M, Short, A, Miosge, L, Barthel, N, Teh, CE, Roots, CM, Bull, KR, Jeelall, Y, Horikawa, K, Whittle, B, Balakishnan, B, Sjollema, G, Bertram, EM, Mackay, F, Rimmer, AJ, Cornall, RJ,  Field, MA, Andrews, TD, Goodnow, CC and Enders, A., 2013, B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8- dendritic cells require the intramembrane endopeptidase SPPL2A. The Journal of experimental medicine  210:31-40.  
                           
  7. Enders, A, Stankovic, S, Teh, C, Uldrich, AP, Yabas, M, Juelich, T, Altin, JA, Frankenreiter, S, Bergmann, H, Roots, CM, Kyparissoudis, K, Goodnow, CC and Godfrey, DI., 2012, ZBTB7B (Th-POK) regulates the development of IL-17-producing CD1d-restricted mouse NKT cells. Journal of immunology 189:5240-9.
     
  8. Yabas, M, Teh, CE, Frankenreiter, S, Lal, D, Roots, CM, Whittle, B, Andrews, DT, Zhang, Y, Teoh, NC, Sprent, J, Tze, LE, Kucharska, EM, Kofler, J, Farell, GC, Bröer, S, Goodnow, CC and Enders, A., 2011,  ATP11C is critical for the internalization of phosphatidylserine and differentiation of B lymphocytes. Nature Immunology 12:441-449.       
               
  9. Teh, CE, Daley, SR, Enders, A* and Goodnow, CC* (* Equal contribution)., 2010, T-cell regulation by casitas B-lineage lymphoma  (Cblb) is a critical failsafe against autoimmune disease due to autoimmune regulator (Aire) deficiency. Proceedings of the National Academy of Sciences of the United States of America.

Updated:  18 August 2018/Responsible Officer:  Director, JCSMR/Page Contact:  Web Manager