Medicine and Health Sciences Commons^™

Checkpoint Inhibitor Immune-Related Adverse Events: A Focused Review On Autoantibodies And B Cells As Biomarkers, Advancements And Future Possibilities, John Taylor, Aesha Gandhi, Elin Gray, Pauline Zaenker

Research outputs 2022 to 2026

The use of immune checkpoint inhibitors (ICIs) has evolved rapidly with unprecedented treatment benefits being obtained for cancer patients, including improved patient survival. However, over half of the patients experience immune related adverse events (irAEs) or toxicities, which can be fatal, affect the quality of life of patients and potentially cause treatment interruption or cessation. Complications from these toxicities can also cause long term irreversible organ damage and other chronic health conditions. Toxicities can occur in various organ systems, with common observations in the skin, rheumatologic, gastrointestinal, hepatic, endocrine system and the lungs. These are not only challenging to manage …

What Do We Know So Far About Ofatumumab For Relapsing Multiple Sclerosis? A Meta-Analytical Study, Hafiza Munazza Taj, Maryam Talib, Sania Siddiqa, Azza Sarfraz, Zouina Sarfraz, Karla Robles-Velasco, Ivan Cherrez-Ojeda

Department of Paediatrics and Child Health

Ofatumumab is a monoclonal antibody that reduces the level of B cells that alter the progression of relapsing multiple sclerosis. Originally approved by the Food and Drug Administration (FDA) in August 2020, this meta-analysis determines the outcomes of four randomized controlled trials (RCTs) for endline outcomes of Gadolinium-enhancing T1 lesions on MRI scans reported as Cohen's d and relapse rate reported as risk ratio. All four RCTs reported favorable findings of gadolinium-enhancing T1 lesions (Cohen's d = -0.44, p < 0.00001). The relapse rate was reduced by 46% post ofatumumab administration (RR = 0.54, p < 0.00001). With 14 ongoing trials in this area, more data is required to consolidate our findings.

The Role Of Reactive Oxygen Species In The Accumulation Of Driver Mutations In B Cell Acute Lymphoblastic Leukemia, Mia P. Sams

Electronic Thesis and Dissertation Repository

B cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with recurrent mutations and high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine was tested for its ability to prolong lifespan of a mouse model of B-ALL and reduce frequency of mutations. Mice treated with 1g/L of N-acetylcysteine in drinking water were found to have delayed onset of B-ALL at 11 weeks of age and changes in gene expression relating to B cell development, calcium-apoptosis signaling, and pathways in cancer, although no differences in lifespan were observed. Tumours from treated …

The Role Of Rna Helicase Rhau In Immunoglobulin Class Switch Recombination, Sabine Jean Guillaume

Dissertations and Theses

B cells alter the expression of immunoglobulin isotypes through a process known as class switch recombination (CSR). In these cells, activation induced cytidine deaminase (AID) binds Gquadruplex (G4) switch transcripts, which serve as guide RNAs to target AID to the immunoglobulin heavy chain switch (S) regions in the DNA for CSR. Sequence alignment revealed homology between the AID G4 binding domain and the RNA helicase associated with AU-rich element (RHAU) specific motif (RSM), which allows RHAU binding to G4 RNAs and subsequent unwinding of G4 RNA into single-stranded transcripts. We hypothesize that RHAU functions in CSR by binding G4 S …

Inhibition Of Bruton Tyrosine Kinase Reduces Neuroimmune Cascade And Promotes Recovery After Spinal Cord Injury, Chen Guang Yu, Vimala Bondada, Hina Iqbal, Kate L. Moore, John C. Gensel, Subbarao Bondada, James W. Geddes

Physiology Faculty Publications

Microglia/astrocyte and B cell neuroimmune responses are major contributors to the neurological deficits after traumatic spinal cord injury (SCI). Bruton tyrosine kinase (BTK) activation mechanistically links these neuroimmune mechanisms. Our objective is to use Ibrutinib, an FDA-approved BTK inhibitor, to inhibit the neuroimmune cascade thereby improving locomotor recovery after SCI. Rat models of contusive SCI, Western blot, immunofluorescence staining imaging, flow cytometry analysis, histological staining, and behavioral assessment were used to evaluate BTK activity, neuroimmune cascades, and functional outcomes. Both BTK expression and phosphorylation were increased at the lesion site at 2, 7, 14, and 28 days after SCI. Ibrutinib …

Engineering B Cells For Use In Immunotherapy And Cancer, Emily Ensley

Dissertations & Theses (Open Access)

B cells can be divided into effector and regulatory immune cells. While effector B cells are key drivers of humoral immunity due to their ability to generate antibodies specific to pathogens, regulatory B cells (Bregs) have recently been shown to control inflammatory responses in multiple diseases through the production of anti-inflammatory cytokines, including interleukin (IL)-10, IL-35 and transforming growth factor-beta (TGF-b). Ex vivo expansion of B cells has been challenging due to their tendency to undergo apoptosis in culture. Thus, creating a successful expansion protocol with exceptional viability will open the door for B cells to be used directly for …

Viral Factors Influencing Early Infection Events During Ex-Vivo Kshv Infection, Ramina Nabiee

Pharmaceutical Sciences (PhD) Dissertations

The enigma of Kaposi Sarcoma Herpes Virus infection, and its persistence despite a quarter century of research on the virus, has given rise to an immediate need for addressing fundamental questions about basic immunology and virology knowledge regarding this virus. Kaposi Sarcoma Herpes Virus (KSHV), also known as Human Herpesvirus 8 (HHV8), is the etiological agent of Kaposi Sarcoma (KS) and other lymphoproliferative cancers, such as Multicentric Castleman’s Disease (MCD), Primary Effusion Lymphoma (PEL), and a newly discovered rare disease called KSHV Inflammatory Cytokines Syndrome (KICS). Epidemic KS, also known as AIDS-KS, is the most common cancer in untreated HIV …

Progress In The Therapy Of Myasthenia Gravis: Getting Closer To Effective Targeted Immunotherapies, Marinos Dalakas

Department of Neurology Faculty Papers

PURPOSE OF REVIEW: To provide an update on immunomodulating and immunosuppressive therapies in myasthenia gravis and highlight newly approved, or pending approval, therapies with new biologics.

RECENT FINDINGS: Preoperative IVIg is not needed to prevent myasthenic crisis in stable myasthenia gravis patients scheduled for surgery under general anesthesia, based on controlled data. Rituximab, if initiated early in new-onset myasthenia gravis, can lead to faster and more sustained remission even without immunotherapies in 35% of patients at 2 years. Biomarkers determining the timing for follow-up infusions in Rituximab-responding AChR-positive patients are discussed. Most patients with MuSK-positive myasthenia gravis treated with Rituximab …

Bst2 Isoforms: Distribution And Potential Use In Cancer Therapeutics, Ahmed Muhsin

Dissertations & Theses (Open Access)

Identifying a cancer-specific cellular target is one of the key factors that can pave a “bench to the bedside” path of a target therapy. Bone marrow stromal cell antigen 2 (BST2) is a raft-associated type II transmembrane protein with an unusual topology. Analyses showed a variable degree of BST2 expression in most organs. Two research groups identified different BST2 isoforms of BST2 generated by posttranscriptional modification. In this research, I studied the long BST2 isoform’s distribution in breast tissue and B cell lines using the novel monoclonal antibody (MAb) LA5, an anti-BST2-long MAb. This approach revealed the expression of the …

B Cells Migrate Into Remote Brain Areas And Support Neurogenesis And Functional Recovery After Focal Stroke In Mice, Sterling B. Ortega, Vanessa O. Torres, Sarah E. Latchney, Cody W. Whoolery, Ibrahim Z. Noorbhai, Katie Poinsatte, Uma M. Selvaraj, Monica A. Benson, Anouk J. M. Meeuwissen, Erik J. Plautz, Xiangmei Kong, Denise M. Ramirez, Apoorva D. Ajay, Julian P. Meeks, Mark P. Goldberg, Nancy L. Monson, Amelia J. Eisch, Ann M. Stowe

Neurology Faculty Publications

Lymphocytes infiltrate the stroke core and penumbra and often exacerbate cellular injury. B cells, however, are lymphocytes that do not contribute to acute pathology but can support recovery. B cell adoptive transfer to mice reduced infarct volumes 3 and 7 d after transient middle cerebral artery occlusion (tMCAo), independent of changing immune populations in recipient mice. Testing a direct neurotrophic effect, B cells cocultured with mixed cortical cells protected neurons and maintained dendritic arborization after oxygen-glucose deprivation. Whole-brain volumetric serial two-photon tomography (STPT) and a custom-developed image analysis pipeline visualized and quantified poststroke B cell diapedesis throughout the brain, including …

Cd4 T Follicular Helper Cells Prevent Depletion Of Follicular B Cells In Response To Cecal Ligation And Puncture, M. D. Taylor, M. R. Brewer, A. Nedeljkovic-Kurepa, Y. Yang, K. S. Reddy, M. N. Abraham, B. J. Barnes, C. S. Deutschman

Journal Articles

No abstract provided.

A Pilot Study Identifying Brain-Targeting Adaptive Immunity In Pediatric Extracorporeal Membrane Oxygenation Patients With Acquired Brain Injury, Sterling B. Ortega, Poornima Pandiyan, Jana Windsor, Vanessa O. Torres, Uma M. Selvaraj, Amy Lee, Michael Morriss, Fenghua Tian, Lakshmi Raman, Ann M. Stowe

Neurology Faculty Publications

OBJECTIVES: Extracorporeal membrane oxygenation provides short-term cardiopulmonary life support, but is associated with peripheral innate inflammation, disruptions in cerebral autoregulation, and acquired brain injury. We tested the hypothesis that extracorporeal membrane oxygenation also induces CNS-directed adaptive immune responses which may exacerbate extracorporeal membrane oxygenation-associated brain injury.

DESIGN: A single center prospective observational study.

SETTING: Pediatric and cardiac ICUs at a single tertiary care, academic center.

PATIENTS: Twenty pediatric extracorporeal membrane oxygenation patients (0-14 yr; 13 females, 7 males) and five nonextracorporeal membrane oxygenation Pediatric Logistic Organ Dysfunction score matched patients.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: Venous blood samples were …

Role Of The Gut Microbiota As A Natural Adjuvant For Vaccine, Nicole Benn, Gerard F. Hoyne

Health Sciences Papers and Journal Articles

Vaccines have provided the most beneficial contribution to public health. Generating antigen specific antibody responses and long lasting memory are crucial for the protective immunity offered by vaccination. Unfortunately, not all individuals respond in the same manner to vaccine formulations. The microbiota is established during postnatal development and remains relatively stable for long periods. Our understanding that the microbiota can have beneficial effects on human health has led immunologists to investigate how these organisms may shape the innate and adaptive immune responses of the host. In this review we examine the impact of the microbiota on the host immune responses …

Plasma Cell Differentiation Pathways In Systemic Lupus Erythematosus, S. Malkiel, A. N. Barlev, Y. Atisha-Fregoso, J. Suurmond, B. Diamond

Journal Articles

No abstract provided.

Spotlight On Blisibimod And Its Potential In The Treatment Of Systemic Lupus Erythematosus: Evidence To Date, Aleksander Lenert, Timothy B. Niewold, Petar Lenert

Internal Medicine Faculty Publications

B cells in general and BAFF (B cell activating factor of the tumor necrosis factor [TNF] family) in particular have been primary targets of recent clinical trials in systemic lupus erythematosus (SLE). In 2011, belimumab, a monoclonal antibody against BAFF, became the first biologic agent approved for the treatment of SLE. Follow-up studies have shown excellent long-term safety and tolerability of belimumab. In this review, we critically analyze blisibimod, a novel BAFF-neutralizing agent. In contrast to belimumab that only blocks soluble BAFF trimer but not soluble 60-mer or membrane BAFF, blisibimod blocks with high affinity all three forms of BAFF. …

Endogenous Interferon-Β Regulates Survival And Development Of Transitional B Cells, Jennie Ann Hamilton

All ETDs from UAB

The survival responses of transitional B cells play a key role in shaping the development of mature, antibody producing B cells. Abnormal transitional T1 B cell survival responses are associated with the generation of polyreactive self-antigen-reactive mature B cells in systemic lupus erythematosus (SLE). Type I interferon (IFN) dysregulation is strongly associated with autoantibodies (autoAbs) and disease flares, particularly in African American (AA) patients. B cells produce a variety of immune-modulatory cytokines, but B cell production of high affinity IFNβ in SLE has not been investigated. In the present study, analysis of PBMCs from SLE patients (n=34) and healthy controls …

Transcriptome Analysis Of B Cell Immune Functions In Periodontitis: Mucosal Tissue Responses To The Oral Microbiome In Aging, Jeffrey L. Ebersole, Sreenatha S. Kirakodu, Michael John Novak, Luis Orraca, Janis Gonzalez-Martinez, Larry Cunningham Jr., Mark V. Thomas, Arnold J. Stromberg, Subramanya N. Pandruvada, Octavio A. Gonzalez

Center for Oral Health Research Faculty Publications

Evidence has shown activation of T and B cells in gingival tissues in experimental models and in humans diagnosed with periodontitis. The results of this adaptive immune response are noted both locally and systemically with antigenic specificity for an array of oral bacteria, including periodontopathic species, e.g., Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. It has been recognized through epidemiological studies and clinical observations that the prevalence of periodontitis increases with age. This report describes our studies evaluating gingival tissue transcriptomes in humans and specifically exploiting the use of a non-human primate model of naturally occurring periodontitis to delineate gingival mucosal …

The Roles Of Il-21 And Il-10 In Cellular And Humoral Immune Responses, Yuan Tian

All ETDs from UAB

Protective immunity mediated by cellular and humoral immune responses relies on the ability of T cells and B cells to generate both effector cells that cooperate to eliminate antigens and memory cells that can survive for long periods with enhanced abilities to control recurring antigens. Thus, understanding the factors that regulate the development of T cell and B cell responses can improve the development of vaccines and immunotherapies against infectious diseases and cancers. Cytokines play important roles in regulating T cell and B cell responses, and in this thesis I have investigated the functions of two cytokines, interleukin (IL)-21 and …

The Role Of Alternative Splicing In The Control Of Immune Homeostasis And Cellular Differentiation, Mehmet Yabas, Hannah Elliott, Gerard F. Hoyne

Health Sciences Papers and Journal Articles

Alternative splicing of pre-mRNA helps to enhance the genetic diversity within mammalian cells by increasing the number of protein isoforms that can be generated from one gene product. This provides a great deal of flexibility to the host cell to alter protein function, but when dysregulation in splicing occurs this can have important impact on health and disease. Alternative splicing is widely used in the mammalian immune system to control the development and function of antigen specific lymphocytes. In this review we will examine the splicing of pre-mRNAs yielding key proteins in the immune system that regulate apoptosis, lymphocyte differentiation, …

Late Stages Of Hematopoiesis And B Cell Lymphopoiesis Are Regulated By Α-Synuclein, A Key Player In Parkinson's Disease, Wenbin Xiao, Afshin Shameli, Clifford V. Harding, Howard J. Meyerson, Robert W. Maitta

Faculty Scholarship

α-Synuclein plays a crucial role in Parkinson's disease and dementias defined as synucleinopathies. α-Synuclein is expressed in hematopoietic and immune cells, but its functions in hematopoiesis and immune responses are unknown. We utilized α-synuclein(-/-) (KO) mice to investigate its role in hematopoiesis and B cell lymphopoiesis. We demonstrated hematologic abnormalities including mild anemia, smaller platelets, lymphopenia but relatively normal early hematopoiesis in KO mice compared to wild-type (WT) as measured in hematopoietic stem cells and progenitors of the different cell lineages. However, the absolute number of B220(+)IgM(+) B cells in bone marrow was reduced by 4-fold in KO mice (WT: …

B Cell Tolerance In Health And Disease, Murali Gururajan, Vishal J. Sindhava, Subbarao Bondada

Microbiology, Immunology, and Molecular Genetics Faculty Publications

B lymphocyte receptors are generated randomly during the bone marrow developmental phase of B cells. Hence, the B cell repertoire consists of both self and foreign antigen specificities necessitating specific tolerance mechanisms to eliminate self-reactive B cells. This review summarizes the major mechanisms of B cell tolerance, which include clonal deletion, anergy and receptor editing. In the bone marrow presentation of antigen in membrane bound form is more effective than soluble form and the role of dendritic cells in this process is discussed. Toll like receptor derived signals affect activation of B cells by certain ligands such as nucleic acids …

Intrinsic And Extrinsic Factors Required For Cd4 T Memory Cell Formation And Function, Sarah B. Mollo

All ETDs from UAB

CD4 T cells are central to the organization of the immune response through the secretion of cytokines that recruit and activate other immune cells. Following infection and pathogen control, the majority of the effector CD4 T cells undergo apoptosis, leaving a subset that persists and gives rise to the memory T cell pool. Upon encountering the same pathogen, memory CD4 T cells respond rapidly, providing enhanced protection from re-infection. What determines which effector CD4 T cells will survive is unclear; however, there are a number of factors both intrinsic to the cell as well as external signals from the environment …

The Role Of Fyn And B-Cell Expressed Adam10 In Early B Cell Development, Germinal Center Formation And Terminal B Cell Differentiation, Natalia Chaimowitz

Theses and Dissertations

In these studies we sought to determine the role of Fyn kinase and ADAM10 in B cell biology. A disintegrin and metalloproteinase 10 (ADAM10) is a zinc dependent proteinase related to matrix metalloproteinases. ADAM10 has emerged as a key regulator of cellular processes by cleaving and shedding extracellular domains of multiple transmembrane receptors and ligands. In particular, ADAM10 has been identified as a key regulator of lymphocyte development. Here we report that ADAM10 is dispensable for early B cell development within the bone marrow. However, deletion of ADAM10 from all peripheral B cells or in post-switch cells leads to severe …

Modulation Of Autoimmune Diabetes By B Cells Specific For N-Acetyl-D-Glucosamine, Brian L. Dizon

All ETDs from UAB

Type I diabetes (T1D) is an autoimmune disease in which ß cells are destroyed by the immune system; however, role of infections in type I diabetes (T1D) pathogenesis is unclear. Reports suggesting that childhood Group A Streptococcal (GAS) infections protected against T1D prompted us to study how antibodies to N-acetyl-D-glucosamine (GlcNAc), which are induced by GAS infection, influenced T1D development. We found that GlcNAc-specific antibodies reacted with ß cell secretory granules, and neonatal NOD mice immunized with GAS or given GAS-immune sera were protected from spontaneous diabetes. Monoclonal GlcNAc-specific IgM blocked activation and effector responses to islet antigens by diabetogenic …

The Effect Of Total Work Performed During Acute Heavy Resistance Exercise On Circulating Lymphocytes In Untrained Men, Neil A. Kelly Jr

Master's Theses

Lymphocytes are one of many leukocytes which exert a biphasic response to acute intense resistance exercise. Exercise volume (i.e. total work) has been shown to have an immunomodulatory effect. This study evaluates the effect of total work performed during an intense resistance exercise protocol on lymphocyte concentrations in the circulation. Untrained, college-aged (18-35) males who performed high amounts of work (HW) were compared to those who performed low amounts of work (LW). Resistance exercise testing consisted of 6 sets of 10 repetitions of the squat exercise with 2 minutes rest between sets. Both HW and LW performed the same relative …

Development Of A Mucosal Vaccine Protective Against Francisella Tularensis Infection, Amit R. Ashtekar

All ETDs from UAB

Francisella tularensis, a facultative intracellular, gram-negative coccobacillus, is the causative agent of tularemia and has been classified as a category A biological agent. Since there currently is no licensed vaccine available, in this study, we assessed the potential of a bivalent subunit vaccine comprising of DnaK and Tul4 to protect against respiratory tularemia. Intranasal immunization of C57BL/6 mice with DnaK, Tul4, and the adjuvant GPI-0100 resulted in mucosal and systemic antibody responses to DnaK and Tul4. In addition to antibody responses, this immunization regimen also induced both Th1 and Th2 cell-mediated immune responses specific for DnaK and Tul4. Finally, more …

Identification Of B-Cell Epitopes On Domain 4 Of Anthrax Protective Antigen, Cassandra D. Kelly-Cirino

Legacy Theses & Dissertations (2009 - 2024)

Protective Antigen (PA) is the receptor binding subunit common to both Lethal (LT) and Edema (ET) toxins, which contribute to the mortality associated with Bacillus anthracis infection. While recombinant PA (rPA) is likely to be an important constituent of second generation anthrax vaccines, evaluating the effectiveness of candidate vaccines is currently difficult, because the specific B cell epitopes involved in toxin neutralization have not been completely defined. The only well characterized antibody, 14B7, has been shown to disrupt the association of PA with the anthrax toxin receptors (ATR) by binding to domain 4 of PA. I hypothesized that other domain …

Golgi Specificity And Development Of Autoreactive B Cells, Fazlullah Salar Khan Nawazi

Theses and Dissertations (ETD)

B cell receptors with certain heavy/light chain pairs predominate in the periphery of anti-DNA heavy chain transgenic mice while certain other B cell receptors are absent. We wanted to know why. To answer this, we re-constructed B cell receptors represented in the anti-DNA transgenic mice by cloning them as single chain variable fragments (scFv) to analyze their affinity to dsDNA. scFv representing receptors that were recovered from the spleens of transgenic mice had very little to no affinity to dsDNA. scFv representing receptors that were absent in the spleen had high affinity to dsDNA. We therefore concluded that receptors with …

Expression Of The Autoimmune Fcgr2b Nzw Allele Fails To Be Upregulated In Germinal Center B Cells And Is Associated With Increased Igg Production, S.M. Ziaur Rahman, H. Niu, D. Perry, Timothy L. Manser, L. Morel

Department of Microbiology and Immunology Faculty Papers

The inhibitory receptor FcγRIIb regulates B-cell functions. Genetic studies have associated Fcgr2b polymorphisms and lupus susceptibility in both humans and murine models, in which B cells express reduced FcγRIIb levels. Furthermore, FcγRIIb absence results in lupus on the appropriate genetic background, and lentiviral-mediated FcγRIIb overexpression prevents disease in the NZM2410 lupus mouse. The NZM2410/NZW allele Fcgr2b is, however, located in-between Sle1a and Sle1b, two potent susceptibility loci, making it difficult to evaluate Fcr2bNZW independent contribution. By using two congenic strains that each carries only Sle1a (B6.Sle1a(15–353)), or Fcr2bNZW in the absence of Sle1a or Sle1b (B6.Sle1(111–148)), we show that the …

The Absence Of Cd20 Messenger Rna In Recurrent Cutaneous B-Cell Lymphoma Following Rituximab Therapy, Yeshwant B. Rawal, Gerard J. Nuovo, Gwyn E. Frambach, Pierluigi Porcu, Robert A. Baiocchi, Cynthia M. Magro

School of Dentistry Faculty Research and Publications

Background: Rituximab has been used to treat relapsed low-grade or advanced non-Hodgkin's lymphoma since 1997, targeting the CD20 antigen expressed by B cells. Single-agent rituximab therapy is safe and well tolerated. Recurrences showing a loss of CD20 expression following rituximab therapy have been reported.

Methods: Four patients with CD20-positive cutaneous B-cell lymphoma received rituximab therapy with subsequent recurrences. The biopsies were assessed for cytoplasmic CD20 expression; CD20 messenger RNA was also assessed where tissue was available.

Results: Cutaneous relapses occurring within 1.5–3 months following the last dose of rituximab were CD20 negative. In three cases, subsequent relapses showed renewed expression …