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Principal Investigator: Alkesh Harihar Jani
Organization: VA EASTERN COLORADO HEALTH CARE SYSTEM
Fiscal Year: 2022
Funding agency: Veterans Affairs
Bacterial infections are the second leading cause of death in ESRD. The incidence of pneumonia amongst
dialysis patients is increasing and leads to a mortality rate that is 14-16-fold greater than pneumonia in the
general population. Little is known regarding the immune response to pneumococcal vaccination in patients with
CKD and ESRD. Preliminary data suggests that antibody production and duration in response to pneumococcal
vaccines is reduced in CKD and ESRD. The cause of decreased antibody production and duration in response
to pneumococcal vaccines is unknown.
CKD and ESRD may impair B cells directly and reduce the ability of T follicular helper (TFH) cells to
support effective B cell selection and differentiation. Production of antibodies of high specificity, affinity, and,
thus, function is derived from the frequency and pattern of mutation in immunoglobulin genes that encode the
antibody’s antigen-binding variable region (VH) in response to infection or vaccine. Development of effective
antibodies requires serial mutations in VH genes by somatic hypermutation (SHM) and changes in the effector
constant region from IgM to IgG or IgA by class switch recombination. Both processes require the DNA editing
enzyme AID (activation-induced cytidine deaminase) in B cells in lymphoid germinal centers (GC). The effect
of CKD on B cell maturation, SHM, class switch recombination and AID is unknown.
We will characterize mucosal (nasopharyngeal) and systemic B cell and antibody responses to PCV-13 among
adults with CKD and determine:
a) Whether CKD impairs levels of PPS-specific IgA and IgG in nasal mucosa and in blood with PCV-13, and
differential expression of specific IgG1/2 and IgA1/2;
b) Whether the quality (avidity) and function (opsonophagocytosis) of PPS-specific mucosal (nasopharyngeal)
and systemic IgA and IgG are compromised by CKD.
c) If PPS-specific IgG1/2 (and IgA1/2) show differential i) production with PCV-13 with CKD in blood and
nasopharyngeal mucosa. ii) killing of S. pneumoniae.
We will determine whether CKD impacts the mutation frequency of VH genes in PPS-specific B cells in
association with impaired TFH and AID responses after PCV-13 vaccination.
a) Characterize the frequency, diversity, clustering and VH gene mutation frequency in pneumococcal capsule-
specific IgG antibody-secreting cells in each group on day 7 after PCV-13;
b) Determine TFH cell recruitment and activity, expression of AID in B cell subsets pre- and post-stimulation by i)
mRNA for AID and ii) intracellular AID protein expression.
c) Determine the contribution of chronic inflammation (eg., IL-6, TNF-α) in CKD on TFH and AID responses and
capsule-specific antibody levels, avidity, function after PCV-13.
Terms: <(TNF)-α><19S Gamma Globulin><21+ years old><7S Gamma Globulin><AICDA><AICDA protein><AID gene><AID protein><Ab response><Adult><Adult Human><Affect><Affinity><Age-Years><Airway mucosa><American><Antibodies><Antibody Formation><Antibody Production><Antibody Response><Antibody-Secreting Cells><Avidity><B blood cells><B cell><B cell differentiation factor><B cell growth factor><B cell stimulating factor 2><B cells><B-Cell Differentiation Factor><B-Cell Differentiation Factor-1><B-Cell Differentiation Factor-2><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><B-Cell Stimulatory Factor-2><B-Cell Subsets><B-Cells><B-Lymphocyte Subsets><B-Lymphocytes><B-cell><BCDF><BCDF-1><BCGF><BCGF-1><BCSF 1><BSF-1><BSF-2><BSF1><BSF2><Bacteria><Bacterial Infections><Bacterial Pneumonia><Binetrakin><Blood><Blood Reticuloendothelial System><CD154><CD40L><CD40LG><CDA2 protein><Cachectin><Capsules><Caring><Cause of Death><Cell Communication><Cell Interaction><Cell Maturation><Cell Nucleus><Cell-to-Cell Interaction><Chronic><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Class Switching><Class Switchings><Constant Region><Cytoplasm><D pneumoniae><D. pneumoniae><DNA><Data><Defect><Deoxyribonucleic Acid><Development><Dialysis><Dialysis patients><Dialysis procedure><Diplococcus pneumoniae><ESRD><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Enzyme Activation><Frequencies><Gene Alteration><Gene Mutation><General Population><General Public><Genes><Genetic Alteration><Genetic Change><Genetic defect><Germinal Center><Glycans><HPGF><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hepatocyte-Stimulating Factor><Hospital Admission><Hospitalization><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-4><IL-6><IL4 Protein><IL6 Protein><Ig Constant Region><Ig Genes><Ig Somatic Hypermutation><IgA><IgA1><IgG><IgG1><IgM><Immune response><Immunoglobulin A><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunoglobulin Constant Region><Immunoglobulin G><Immunoglobulin Genes><Immunoglobulin Isotype-Switch Recombination><Immunoglobulin M><Immunoglobulin Somatic Hypermutation><Immunoglobulin Switch Recombination><Immunoglobulin-Secreting Cells><Immunological response><Impairment><Incidence><Inducer Cells><Inducer T-Lymphocytes><Infection><Inflammation><Interleukin-4><Interleukin-4 Precursor><Interleukin-6><Isotype Switching><Isotype Switchings><Kidney Diseases><Lead><Lobar Pneumonia><Lymphocyte Stimulatory Factor 1><Lymphoid><MCGF-2><MGI-2><Macrophage-Derived TNF><Mast Cell Growth Factor-2><Messenger RNA><Monocyte-Derived TNF><Mucosa><Mucosal Tissue><Mucous Membrane><Mutation><Myeloid Differentiation-Inducing Protein><Nasal Mucosa><Nephropathy><Nuclear><Nucleus><Patients><Pattern><Pb element><Persons><Plasmacytoma Growth Factor><Pneumococcal Pneumonia><Pneumococcal Polysaccharide Vaccine><Pneumococcal conjugate vaccine><Pneumococcal vaccine><Pneumococcus><Pneumonia><Pneumovax 23><Pnu-Imune 23><Polysaccharides><Polyvalent pneumococcal vaccine><Population><Process><Production><Proteins><Recruitment Activity><Renal Disease><Respiratory Mucosa><S pneumoniae><S. pneumoniae><Specificity><Streptococcus pneumoniae><Streptococcus pneumoniae vaccine><Structure of germinal center of lymph node><Structure of mucous membrane of nose><Switch Recombination><T-Cell Growth Factor 2><T-Cells><T-Lymphocyte><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFSF5><TNFSF5 gene><TNFα><TRAP Gene><Therapeutic><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Vaccination><Vaccines><Veterans><activation-induced cytidine deaminase><activation-induced deaminase><active recruitment><adulthood><antibody biosynthesis><antigen antibody binding><antigen binding><antigen bound><bacteria infection><bacteria pneumonia><bacterial disease><capsule><chronic kidney disease><develop a vaccine><develop vaccines><development of a vaccine><developmental><dialysis therapy><differential expression><differentially expressed><experiment><experimental research><experimental study><fighting><genome mutation><heavy metal Pb><heavy metal lead><host response><immune system response><immunoglobulin biosynthesis><immunoresponse><improved><interferon beta 2><kidney disorder><mRNA><mortality><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><outcome following vaccination><outcome following vaccine><protein expression><renal disorder><response><result following vaccination><result following vaccine><somatic hypermutation><thymus derived lymphocyte><transcriptional differences><vaccination outcome><vaccination result><vaccine development><vaccine outcome><vaccine response><vaccine responsiveness><vaccine result><vaccine-induced response>