Immunoglobulin is a highly diverse self-molecule that improves cellular diversity and function during immune reconstitution
Introduction
Many are yet the clinical observations that remain without a rationale or clear explanation. A general concept in immunology is that B and T cells develop independently. Primary B cell immunodeficiencies, as Bruton’s syndrome, are said to progress with a normal T cell compartment. However, it is common for these patients to develop severe viral or fungi infections, which are common in T cell disorders. Another clinical observation without a clear rationale relates to the therapeutics of viral infections, as cytomegalovirus, which includes intravenous immunoglobulin (IVIg) besides the antiviral agent. There is not an unequivocal and clear explanation for adding IVIg in these situations.
A competent adaptive immune system relies on proficient lymphocytes that need to be present in an appropriate number and to comprise a vast repertoire of diverse T and B cell receptors. These properties grant the immune system with the ability to recognize and react against potentially any foreigner antigen and to respond more rapidly and effectively to pathogens that have been encountered previously. B and T compartments of the immune system are known to cooperate in their function in the periphery but their development is commonly understood as independent. T lymphocytes constitute a “cellular” arm of adaptive immunity and its compartment comprises a “repertoire” of approximately 109 distinct clones identified by their T cell receptor (TCR) [1]. Each clone is capable of recognizing at least one and, in most cases, several different peptides. A more diverse TCR repertoire assures a greater likelihood that, at least, one clone of T cells will recognize and develop protective immunity against a broad range of bacteria, viruses, toxins and tumors that threaten health [2], [3], [4] and this is the basis of cellular immune competence.
Despite major advances in the understanding of the immune system, current immunological therapies rely on immune suppression, target immune response or unspecific immune activation. Although a vigorous immune system has a superior ability to fight attacks to the individual body in case of infections, transplants, or neoplasm invasion, there are currently no therapies able to improve general immunity. Maintenance and increase of immunity could prevent complications of primary and acquired immunodeficiency disorders including AIDS and malnutrition, to reverse the natural deterioration of immunity associated with aging, to allow safer use of therapies for cancer which are myeloablative and myelosuppressive, to allow safer use of regimens aiming immunological tolerance and maybe to fight infection more effectively.
We propose the hypothesis that immunoglobulin is a highly diverse self-molecule that improves repertoire diversity during cellular development and immune reconstitution. This hypothesis is based on observations from basic science experiments, contributes to explain previously unexplained clinical observations and may have profound implications for clinical practice and therapy.
Section snippets
How does immunoglobulin contributes to lymphocyte repertoire diversification during development and supports cellular function and maintenance in the periphery
The repertoire of T cells is tailored during T cell development in the thymus. In the thymus, maturing thymocytes first rearrange their TCR chain genes followed by a stringent selection process, which requires that the newly formed TCR recognize the self-MHC/self-peptide complex with low/intermediate avidity in order to survive (reviewed in [5]). The generation of a wide TCR repertoire diversity is dependent on the diversity of the antigens presented in the thymus [6], [7]. B cells are the
Support, testing and clinical implications of this hypothesis
Thus, Ig emerges as essential to the selection of both B and T cell repertoires and a natural highly diverse self-molecule that warrants diversity of the adaptive immune system. This hypothesis gives a new light to the function of natural antibodies that cross the placenta from the mother to the fetus as promoting diversity selection during T and B cell development before birth. Also, this hypothesis contributes to the explanation why it is effective to use IVIg against cytomegalovirus
References (26)
- et al.
Asymptomatic primary Epstein–Barr virus infection occurs in the absence of blood T-cell repertoire perturbations despite high levels of systemic viral load
Blood
(2001) - et al.
Thymic selection by a single MHC/peptide ligand produces a semidiverse repertoire of CD4+ T cells
Immunity
(1997) - et al.
Early lymphocyte recovery predicts superior survival after autologous hematopoietic stem cell transplantation in multiple myeloma or non-Hodgkin lymphoma
Blood
(2001) - et al.
Immune reconstitution and immunotherapy after autologous hematopoietic stem cell transplantation
Blood
(1998) - et al.
A direct estimate of the human ab T cell receptor diversity
Science
(1999) - et al.
T cell repertoire in primary biliary cirrhosis: a common T cell clone and repertoire change after treatment
J Clin Immunol
(2001) - et al.
Immunohistochemical analysis of the T-cell receptor beta-chain variable regions expressed by T lymphocytes infiltrating primary human melanoma
Lab Invest
(1998) Development of alphabeta T cells in the human thymus
Nature Rev Immunol
(2002)- et al.
Requirement for diverse, low-abundance peptides in positive selection of T cells
Science
(1999) - et al.
B cell-dependent TCR diversification
J Immunol
(2004)
Immunoglobulin promotes the diversity and the function of T cells
Eur J Immunol
Normal serum immunoglobulins participate in the selection of peripheral B-cell repertoires
Proceedings of the national academy of sciences of the United States of America
Selection of the expressed B cell repertoire by infusion of normal immunoglobulin G in a patient with autoimmune thyroiditis
Eur J Immunol
Cited by (12)
Thymus repopulation after allogeneic reconstitution in hematological malignancies
2007, Experimental HematologyCitation Excerpt :Taking our data into account, which strongly argue for the necessity to establish central tolerance as a platform for tumor vaccination, this knowledge on T-lineage early progenitor cells, which can be isolated from the bone marrow, could well pave the way for vaccination in the allogeneically reconstituted host. Anti-idiotype antibodies are a therapeutic option in B-cell malignancies [80,81], the efficacy of which we tried to explore in combination with allogeneic BMC reconstitution. We hypothesized that an anti-idiotype may be effective independent of donor-derived T-cell tolerance.
Immune response regulation by antigen receptors' clone-specific nonself parts
2018, Frontiers in ImmunologyAntigen receptor–intrinsic non-self: The key to understanding regulatory lymphocyte–mediated idiotypic control of adaptive immune responses
2016, Critical Reviews in ImmunologyFrequency patterns of T-cell exposed amino acid motifs in immunoglobulin heavy chain peptides presented by MHCs
2014, Frontiers in ImmunologyBroadened T-cell repertoire diversity in ivIg-treated SLE patients is also related to the individual status of regulatory T-cells
2013, Journal of Clinical ImmunologyThe past, present, and future of immune repertoire biology - the rise of next-generation repertoire analysis
2013, Frontiers in Immunology