Immunoglobulin is a highly diverse self-molecule that improves cellular diversity and function during immune reconstitution

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Summary

Paradoxically, human B cell immune deficiencies are associated with increased susceptibility to viral and fungi infections, which are T cell immunity related infections. Also, some viral infections occurring in immune depressed patients such as cytomegalovirus infections are recommended to be treated with intravenous immunoglobulin (IVIg) in combination with antiviral therapy. This fact has no clear biological explanation but it has been shown to be successful.

Recently, B cells and immunoglobulin were identified as essential elements driving T cell receptor (TCR) diversity generation. Idiotype peptides of B cell immunoglobulin may be the driving force for the antigen presenting function of B cells and other antigen presenting cells to influence the T cell repertoire. This seems to be another relevance of Jerne’s idiotypic network and another function of immunoglobulin. Since T cells function depends on the diversity of the TCR repertoire, means to increase the diversity of the T cell repertoire may improve T cell function in situations characterized by a contracted TCR repertoire, such as AIDS, primary immunodeficiency, cancer, autoimmunity and following chemotherapy and hematopoietic precursors transplantation. The clinical hypothesis here put forward is that B cells and/or immunoglobulin may be used therapeutically aiming to increase and potentially to restore T cell repertoire diversity improving T cell function in situations implicating a contracted T cell repertoire. The fact that immunoglobulin influence the composition of T cell repertoire by increasing its diversity allows a much wider application of this molecule in the clinical practice. Here is presented a novel reasoning for the use of IVIg in humans, which should be explored. All the situations where immune reconstitution occurs are potentially a target for this therapeutically mechanism, aiming to fast and improve the diversity of the reconstituted immune repertoires. This new role of Ig molecule, an old and widely therapeutically used molecule, may help to explain several effects that IVIg have in the T cell compartment, such as modulation of the activation and function of effectors T cells. The idea that immunoglobulin is essential in the generation and maintenance of a diverse compartment of T cells, affecting T cell function via that mechanism suggests a promising approach to medical conditions involving immune reconstitution. Furthermore, it represents a new paradigm of understanding the immune system as a complex, interdependent web of cells/cell products that inter-affect each other generation, function and survival.

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

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