BIOSKETCH AND RESEARCH INTERESTSMohamed Khass, PhD, is a post-doctoral fellow in the Division of Clinical Immunology and Rheumatology. Dr. Khass completed a Bachelor’s degree in Pharmacy and a Master’s degree in Biochemistry at Zagazig University in Zagazig, Egypt, which is in the Nile delta. He was recruited to UAB in 2006, and has been mentored by Harry W Schroeder, MD, PhD, since July 2007. After completing his PhD in Microbiology in December of 2012, he decided to continue his studies in Dr. Schroeder’s laboratory at the post-doctoral level.
The Schroeder laboratory is interested in elucidating the mechanisms used to control the development of the antibody repertoire and their role in the pathogenesis of diseases of immune function. Immunoglobulin genes are manufactured during B cell development by the recombinatorial joining of a diverse set of variable (V), diversity (D) and joining (J) gene segments. The diversity of the antigen binding site repertoire is greatly enhanced by the insertion of random nucleotides at the sites of gene segment joining. Although at first glance these mechanisms would appear to create a highly random repertoire of antigen binding sites, closer inspection reveals major biases in the use of individual amino acids at the center of the antigen binding site. These biases make it more difficult to generate broadly neutralizing antibodies against HIV. As a graduate student, Dr. Khass helped show that these biases act to control the production of double stranded DNA binding antibodies of the type found in systemic lupus erythematosus.
As a post-doctoral fellow, his research has been focused on the early stages of B cell development in the bone marrow. In a manuscript just published in the inaugural issue of Science Immunology, he has shown in mice that these biases in the composition of the antigen binding site reflect selection at the pre B cell receptor stage where the immunoglobulin heavy chain is first assessed for functionality. He plans to extend this work into human and to test the role of this selection process in the pathogenesis of acute lymphocytic leukemia.
In working with mice whose immunoglobulin gene loci had undergone gene targeting to alter amino acid biases, Dr. Khass noted that these mice have abnormal skeletons. This has led him to extend his studies to the role of pre B cells in bone development. For this work, which is supported by the Dental Academic Research Training Program (DART), he received the Young Investigator Award at the 2016 annual meeting of the American Society of Bone and Mineral Research.
ABSTRACT
Developmental checkpoints eliminate B cells that synthesize defective immunoglobulin (Ig) heavy (HC) and light (LC) chains. The first checkpoint tests μHCs paired with VpreB/λ5 in a pre-B cell receptor (pre-BCR) to determine whether the μHC will be able to bind conventional LCs to form membrane IgM. VpreB and λ 5 also create a sensing site that interacts with the μHC antigen-binding region complementarity-determining region (CDR)–H3; however, whether this site contributes to Ig repertoire selection and function is unknown. We analyzed the amino acid content of CDR-H3s from HCs cloned from living and apoptotic pre-B cells and from IgG-antigen structures. Using a panel of DH gene–targeted mice, we showed that progressively reducing CDR-H3 tyrosine content increasingly impaired pre-BCR checkpoint passage. Counting from cysteine at framework 3 position 96, we found that VpreB particularly selected for tyrosine at CDR-H3 position 101 and that Y101 also bound antigen in IgG-antigen structures. Therefore, in addition to its stabilization role in the pre-BCR, VpreB also acts as an early invariant antigen by selecting for particular CDR-H3 amino acids. These interactions shape the specificity of the IgG humoral response and may thus impose limitations on development of certain neutralizing antibodies.
Full Manuscript
As a post-doctoral fellow, his research has been focused on the early stages of B cell development in the bone marrow. In a manuscript just published in the inaugural issue of Science Immunology, he has shown in mice that these biases in the composition of the antigen binding site reflect selection at the pre B cell receptor stage where the immunoglobulin heavy chain is first assessed for functionality. He plans to extend this work into human and to test the role of this selection process in the pathogenesis of acute lymphocytic leukemia.
In working with mice whose immunoglobulin gene loci had undergone gene targeting to alter amino acid biases, Dr. Khass noted that these mice have abnormal skeletons. This has led him to extend his studies to the role of pre B cells in bone development. For this work, which is supported by the Dental Academic Research Training Program (DART), he received the Young Investigator Award at the 2016 annual meeting of the American Society of Bone and Mineral Research.
ABSTRACT
Developmental checkpoints eliminate B cells that synthesize defective immunoglobulin (Ig) heavy (HC) and light (LC) chains. The first checkpoint tests μHCs paired with VpreB/λ5 in a pre-B cell receptor (pre-BCR) to determine whether the μHC will be able to bind conventional LCs to form membrane IgM. VpreB and λ 5 also create a sensing site that interacts with the μHC antigen-binding region complementarity-determining region (CDR)–H3; however, whether this site contributes to Ig repertoire selection and function is unknown. We analyzed the amino acid content of CDR-H3s from HCs cloned from living and apoptotic pre-B cells and from IgG-antigen structures. Using a panel of DH gene–targeted mice, we showed that progressively reducing CDR-H3 tyrosine content increasingly impaired pre-BCR checkpoint passage. Counting from cysteine at framework 3 position 96, we found that VpreB particularly selected for tyrosine at CDR-H3 position 101 and that Y101 also bound antigen in IgG-antigen structures. Therefore, in addition to its stabilization role in the pre-BCR, VpreB also acts as an early invariant antigen by selecting for particular CDR-H3 amino acids. These interactions shape the specificity of the IgG humoral response and may thus impose limitations on development of certain neutralizing antibodies.
Full Manuscript