Immunological Reviews最新文献

Human infection with or vaccination against influenza A virus has been one of the most informative systems for understanding how human antibody repertoires recognize viral glycoproteins. Decades of antibody isolation, repertoire sequencing, lineage tracing, serology, viral antigenic evolution, and structural biology have shown that antibody recognition is not simply a matter of “which epitope is targeted.” Instead, each surface on the viral hemagglutinin (HA) presents a distinct structural problem for the immune system. Repeated exposures through infection and vaccination coupled with continuous antigenic drift generate complex immune histories and reveal which viral surfaces evolve under antibody pressure. Structural studies have transformed the field by showing how antibody repertoires solve epitope-specific recognition problems. Some epitopes, such as the HA central stem, recruit highly stereotyped genetic and structural solutions. Others, such as the receptor-binding site, can be approached by genetically diverse antibodies that converge on common structural solutions of receptor mimicry. Additional epitopes, including the lateral patch, anchor, head interface, and head-stem junction, reveal intermediate patterns of repertoire constraint. Together, these examples show that what antibody repertoires “see” is determined by the interplay between viral glycoprotein structure, B cell precursor availability, somatic evolution, and population-level immunoglobulin diversity.

In healthy individuals, autoreactive B cells are normally silenced via central and peripheral tolerance mechanisms. In the periphery, when autoreactive B cells recognize self-antigen via their B cell receptor (BCR) (signal 1) but do not receive T cell help (signal 2), they undergo the tolerance mechanism called anergy. Human anergic B cells are termed B_ND (Naïve IgD+ B cells). Previous studies have shown that B_ND cells are decreased in the peripheral blood of individuals with autoimmunity, suggesting they may have become activated and contributed to the development of disease. In line with this, recently it has been found that a portion of the remaining anergic B cells present in the blood of autoimmune individuals exhibit an activated phenotype. In this review, we will summarize what is known and unknown about these cells, including their relation to other recognized autoreactive B cell subsets, how they become activated in the first place, and what their pathogenic functions are. Understanding how B_ND cells break tolerance and contribute to disease will advance the development of new therapeutic approaches and highlight novel cell populations amenable to depletion.

The development of highly accurate deep learning models for protein structure prediction has transformed the landscape of T-cell receptor (TCR) structure data, which can now be accessed at repertoire scale. We provide a perspective on the growing field of structural TCR immunoinformatics, summarizing core principles of TCR structural biology and highlighting existing resources and tools. We outline computational methods for TCR structure prediction, and discuss outstanding challenges faced by current tools, as well as potential avenues to address these. We expand on the research enabled by the availability of predicted TCR structures, exploring the utility of TCR structure predictions for computationally inferring TCR specificity, as well as summarizing opportunities emerging from the adjacent field of antibody research. Finally, we provide a forward-looking perspective on the advances in deep learning research which have recently enabled computational design of TCRs and TCR-like binders.

As B cells are activated and differentiate into plasma cells, they execute migration programs that allow them to traffic within secondary lymphoid tissues and reach the bone marrow, where they can mature as long-lived plasma cells. Recent studies have revealed mechanisms underlying not only affinity-driven but also isotype-driven plasma cell selection. In addition, the importance of migration programs in plasma cell longevity has become increasingly appreciated. This review focuses on mechanisms that regulate plasma cell numbers and their migration to the bone marrow, with emphasis on our findings and recent advances in related fields.

Autoimmune diseases arise from the breakdown of immune tolerance through complex interactions between genetic predisposition, environmental exposures, and adaptive immune responses. High-throughput T-cell receptor (TCR) repertoire sequencing has transformed our ability to characterize these responses, providing unprecedented insights into clonal dynamics, antigen-driven selection, and immune history. In this review, we summarize the major alterations of TCR repertoires reported across autoimmune diseases, including changes in diversity, clonal expansion, repertoire architecture, and tissue distribution. We discuss the principal biological and technical challenges that currently limit repertoire interpretation, with particular emphasis on the concept that bulk repertoires represent composite mixtures of biologically distinct T-cell populations. Finally, we highlight emerging approaches integrating single-cell profiling, computational modeling, and antigen-specificity inference that are reshaping the field. We propose that TCR repertoires should be viewed as dynamic molecular footprints of autoimmune disease, providing a systems-level framework to improve mechanistic understanding, biomarker discovery, and the development of precision immunotherapies.

Germinal centers (GCs) are specialized microenvironments in which B cells undergo affinity maturation through iterative cycles of somatic hypermutation, proliferation and selection, generating antibodies with improved antigen-binding properties. Although GC B cells do not themselves secrete antibody, they differentiate into memory B cells and plasma cells that provide long-term humoral immunity. GC selection has traditionally been viewed as a process that preferentially expands B cells expressing the highest-affinity B cell receptors. However, recent studies have revealed that physiological GC responses preserve substantial clonal and affinity diversity, and generate plasma cells spanning a broad range of antibody affinities. Here, we review current understanding of the mechanisms governing GC B cell selection and discuss an alternative framework in which T cell help quantitatively refuels GC B cells rather than acting as a binary gate for cyclic re-entry. We further explore how antigen organization, antibody feedback and the biophysical context of antigen recognition may reconcile the apparent discrepancy between affinity-based selection and the maintenance of clonal diversity. Finally, we consider how these concepts may alter our expectations for the plasma cell populations emerging from GCs and discuss their implications for rational vaccine design.

Autoimmune diseases start years before clinical onset. In rheumatoid arthritis (RA), autoantibodies to citrullinated proteins (ACPA) and to modified IgG (rheumatoid factors, RF) can be detected many years before the inflammatory attack on cartilaginous joints. It has been assumed that these antibodies are pathogenic. We show here that many of the antibodies produced before disease onset are protective although there are likely also pathogenic clones directed to cartilaginous joints. To determine the function of these antibodies, it is crucial to analyze them in vivo, which is only possible in mouse models. To ease the translation, we have genetically humanized models which will now allow a more accurate analysis of autoimmune mechanisms in human disease. In this review, we will also discuss what we know today regarding the targeted epitopes and the role of pathogenic and protective antibodies. With this knowledge as the basis, we have developed new types of serologic tests for RA.