Dr. Mongini’s laboratory focuses on the immune system’s B lymphocytes (B cells). It is interested in knowing why B cells, which normally protect the body from microbes by producing antibodies to bacteria and viruses, sometimes become pathogenic and cause disease. Importantly, autoimmune diseases, e.g. lupus, rheumatoid arthritis, multiple sclerosis, affect approximately ~ 14-22 million people (5-8% of the US population). B cells have either a direct or a less well understood indirect role in many of these disorders. Cancer affects ~ 9 million people of which at least 6% are of B lymphocyte origin, e.g. B cell chronic lymphocytic leukemia (B-CLL) and B cell non-Hodgkin’s lymphoma. Thus, understanding how to prevent the abnormal development of pathogenic B cells is a critical challenge. This is particularly so given the aging of the US population and the greater emergence of B cell malignancy and certain autoimmune diseases with increased age.
Dr. Mongini’s laboratory has discovered that upon receiving signals found in inflamed/infected tissues, human B cells can undergo changes that encourage pathogenic behavior. This includes their new expression of molecules that trigger inflammation in other body cells and molecules that cause DNA mutations in B cells. There are reasons to suspect that accrued mutations can lead to abnormal B cell function, in addition to cancer. The lab is presently exploring how an inflammatory lipid, prostaglandin E2 (PGE2) that is produced by both activated B cells and other cells in inflamed tissues can promote DNA mutations in B cells. Through the lab’s illumination of this process, novel approaches for blocking pathogenic B cell development can be tested.
While a strong B cell immune response typically requires the collaboration of B cells with helper T lymphocytes, Dr. Mongini recognized, early in her training as an immunologist, that cells of the innate immune system also could foster B cell responses to antigen. This finding influenced her perspective and promoted her lab’s later discovery that a relatively robust B cell immune response, characterized by several rounds of cell division, could develop when a human B cell encountered antigen in a milieu enriched with molecules secreted by cells of the innate immune system: complement (C3d) and cytokines IL-4/IL-13, BAFF, and APRIL. While this characterization involved in vitro cultures, it is striking that abnormal B cell aggregates develop in several inflamed human tissues, e.g. salivary glands and bronchial tissue, where each of the above molecules is abundantly expressed. In the human autoimmune disorder, Sjogren’s Syndrome, atypical B cell foci in salivary glands are accompanied by production of pathogenic antibodies that target body components and by a high risk of B cell lymphoma.
During the process of unraveling how growth of T cell-independent B cell clones is sustained, the Mongini laboratory, with investigators at New York University School of Medicine, discovered that replicating normal human B lymphocytes upregulate several cyclooxygenase (COX-2) axis molecules strongly linked to inflammation and numerous body malignancies. The proliferating clones produce functionally-relevant levels of prostaglandin E2 (PGE2) – a lipid with important biological effects in inflammatory disease and cancer. This raised the important issue of whether B cell-produced PGE2, or other prostanoids downstream of COX-2, have a role in mediating pathology of B cells and/or neighboring cells.
A continuing focus of the Mongini laboratory is to unravel the diverse effects of PGE2 on B cell behavior. The lab discovered that PGE2 could promote normal human B lymphoblast survival through upregulating anti-apoptotic Mcl-1. This could help explain why activated B cells are often prevalent in sites where COX-2/ PGE2 is highly expressed in other cell lineages. Interestingly, the lab also found that PGE2 signaling accelerates the death of a fraction of replicating cells with elevated DNA damage. Ongoing work suggests that this is in part due to COX-2/ PGE2 promoted expression of an important DNA mutating enzyme within actively dividing lymphoblasts. Importantly, this enzyme, activation-induced cytosine deaminase (AID), provides the B cell lineage with highly diverse receptors for binding pathogens when expressed in a controlled manner, but when uncontrolled can lead to B cell death, to development of pathogenic autoantibody producing B cells and/or to B cell malignancy. The lab’s identification of the PGE2 receptor (EP2) involved in elevating AID suggests a possible means of intervening in B cell AID expression when greater control is needed. This question is being pursued in collaboration with Dr. Ray Dingledine of Emory University School of Medicine. Other studies to investigate how PGE2 signaling through the various B cell-expressed PGE2 receptors influences epigenetic changes within B cell DNA is being initiated in collaboration with Dr. Huidong Shi of Georgia Regent’s University Medical College.
While co-stimuli from the innate immune system can promote short-term clonal expansion of antigen-triggered B cells, most progeny of these clones succumb to activation-induced death – both in culture and in the body. Dr. Mongini’s laboratory has shown that p53, a molecule upregulated during cell stress and DNA damage, contributes significantly to their loss. Importantly, the lab recently reported that these T cell-independent responses are crucibles for the induction of p53 mutations in B cells of certain individuals. While the impact of the observed mutations is presently unknown, certain mutations might circumvent B lymphoblast death either directly or indirectly, through modulating the manner in which B cells communicate with other cells. Because p53 is increasingly recognized as a negative regulator of inflammation, in addition to an important modulator of cell growth/survival, some of these p53 mutations could promote autoimmunity and/or malignancy. Indeed, it is of interest that the majority of point mutations in the B cell malignancy, B-CLL, are found in either the gene for p53 or genes which regulate p53-driven apoptosis. Additionally, B cell lymphomas which develop in inflamed tissues frequently manifest p53 mutations.
The lab is presently examining whether a newly uncovered PGE2 → EP2 signaling pathway for augmented p53 gene transcription may contribute to p53 mutagenesis. From these studies may emerge new approaches to reduce the emergence of certain B cell malignancies with age by attenuating B cell EP2 signaling during periods of chronic inflammation. Importantly, both advancing age and its associated inflammation result in elevated levels of PGE2 within many body tissues.
The lab’s evolving work suggests that both p53 and COX-2 should significantly affect the size and the pathogenic character of B cell clones which develop in chronically inflamed tissues. In this context, it may be relevant that common genetic polymorphisms (SNPs) exist within the human population for each of these genes. Importantly, several SNPs which regulate either p53 function or COX-2 synthesis have been strongly linked with human susceptibility to a variety of disorders. The Mongini lab is interested in investigating how these SNPs affect B cell function both in culture and within diseased individuals. Their influence on susceptibility to B-CLL and/or disease progression is being investigated in collaboration with Drs. Nicholas Chiorazzi, Kanti Rai and other clinical investigators in The Feinstein Institute’s Center for CLL Research and Dr. Eugene Nikitin, Hematology Research Center of Russia.
Northern Arizona University, Flagstaff, AZ
Field of study: Zoology/Chemistry
Stanford University, Stanford, CA
Field of study: Medical Microbiology/Immunology
Tufts University School of Medicine, Boston, MA
Degree: Post-doctoral fellow with Dr. Henry Wortis
Field of study: Immunology
National Institutes of Health, Bethesda, MD
Degree: Post-doctoral fellow with Dr. William Paul
Field of study: Immunology