IgM Repertoire Biodiversity is Reduced in HIV-1 Infection and Systemic Lupus Erythematosus

Abstract

Background: HIV-1 infection or systemic lupus erythematosus (SLE) disrupt B cell homeostasis, reduce memory B cells, and impair function of IgG and IgM antibodies.Objective: To determine how disturbances in B cell populations producing polyclonal antibodies relate to the IgM repertoire, the IgM transcriptome in health and disease was explored at the complementarity determining region 3 (CDRH3) sequence level.Methods: 454-deep pyrosequencing in combination with a novel analysis pipeline was applied to define populations of IGHM CDRH3 sequences based on absence or presence of somatic hypermutations (SHM) in peripheral blood B cells.Results: HIV or SLE subjects have reduced biodiversity within their IGHM transcriptome compared to healthy subjects, mainly due to a significant decrease in the number of unique combinations of alleles, although recombination machinery was intact. While major differences between sequences without or with SHM occurred among all groups, IGHD and IGHJ allele use, CDRH3 length distribution, or generation of SHM were similar among study cohorts. Antiretroviral therapy failed to normalize IGHM biodiversity in HIV-infected individuals. All subjects had a low frequency of allelic combinations within the IGHM repertoire similar to known broadly neutralizing HIV-1 antibodies.Conclusion: Polyclonal expansion would decrease overall IgM biodiversity independent of other mechanisms for development of the B cell repertoire. Applying deep sequencing as a strategy to follow development of the IgM repertoire in health and disease provides a novel molecular assessment of multiple points along the B cell differentiation pathway that is highly sensitive for detecting perturbations within the repertoire at the population level.

The Systemic Lupus Erythematosus Infection Predictive Index (LIPI): A Clinical-Immunological Tool to Predict Infections in Lupus Patients

“…In SLE, naïve B cells may be initially hyper-activated and produce higher levels of anti-dsDNA antibodies but this eventually leads to necroptosis (33), which would explain the lower B cell numbers in our study. Furthermore, in comparison to healthy controls, patients with SLE have lower frequency of BCR sequences with somatic hypermutations (SHM) (34). In animal models, the reduction in naïve B cells promotes Cryptococcus dissemination (35) and the lower biodiversity of BCR sequences with SHM in patients with SLE (34) may diminish the B cell repertoire to combat infections.…”

“…Furthermore, in comparison to healthy controls, patients with SLE have lower frequency of BCR sequences with somatic hypermutations (SHM) (34). In animal models, the reduction in naïve B cells promotes Cryptococcus dissemination (35) and the lower biodiversity of BCR sequences with SHM in patients with SLE (34) may diminish the B cell repertoire to combat infections. Also, the lower pool of naïve B cells could lead to less class-switched memory B cells, which are known to be fundamental in the prevention of infections in other clinical conditions (36).…”

Analysis of immunoglobulin transcripts and hypermutation following SHIVAD8 infection and protein-plus-adjuvant immunization

“…Finally, on the basis of alterations of the human B-cell repertoire after HIV and influenza infection 48 49 , we assessed the effects of Env vaccination and SHIV AD8 infection on V H gene usage. Sundling et al 50 reported relative similarities in V H gene usage between Env-specific and total memory B cells after vaccination, a finding confirmed here.…”

Antibody repertoire analysis in polygenic autoimmune diseases

“…High-throughput sequencing of BCR repertoires from peripheral blood has shown that patients with SLE exhibit increased B-cell clonality compared with heathy individuals. 46,47 This is characterized by polyclonal (multiple) Bcell expansions. 36 This is possibly secondary to increased numbers of plasmablasts.…”