Beginnings of coinhibition.

Costimulatory and coinhibitory mechanisms appear to be involved throughout immune responses to control their specificity and level. Many mechanisms operate; therefore, various theoretical models should be considered complementary rather than competing. One such coinhibitory model, pictured in 1971, involves the crosslinking of antigen receptors with inhibitory Fc receptors by antigen/antibody complexes. This model was prompted by observations that the Fc portion of antibody was required for potent suppression of immune responses by antibody. The signal via the antigen receptor wakes up T or B cells, providing specificity, while costimulators and coinhibitors stimulate or inhibit these awoken cells. The recent observations that administration of monoclonal anti-SARS-CoV-2 spike antibodies in early COVID-19 patients inhibits the induction of clinically damaging autoimmune antibodies suggest they may provide negative Fc signals that are blocked in COVID-19 patients. Furthermore, the reduced ability of SARS-CoV-2 antigen to localize to germinal centres in COVID-19 patients also suggests a block in binding of the Fc of antibody bound to antigen on FcγRIIb of follicular dendritic cells. The distinction between self and foreign is made not only at the beginning of immune responses but also throughout, and involves multiple mechanisms and models. There are past beginnings (history of models) and current and future beginnings for solving serious clinical problems (such as COVID-19) and different types of models used for understanding the complexities of fundamental immunology.

B cell/antibody tolerance to our own antigens.

The lymphoid system normally mounts damaging responses to infectious pathogens while avoiding equally damaging responses to self. A notable number of antibodies to self antigens are formed but normally remain at levels below the damaging threshold, only temporarily rising to damaging levels during protective responses against infectious nonself. Many mechanisms regulate the level of autoantibodies and anti-self B cells including deletion, anergy, ignorance for antigen, receptor editing, coinhibition, competition for resources to sustain B cell responses, and apoptotic denouement of damaging responses following the ejection or containment of foreign invaders. While infectious events may encourage immune responses to self antigens, infectious events tend also to strengthen regulatory mechanisms. When regulatory mechanisms do not function properly, abnormal damaging responses to self antigens may occur. While defects in a single regulatory mechanism may result in autoimmunity, this eventuality usually happens only on permissive genetic backgrounds; this indicates that weakness in other regulatory mechanisms may be necessary to result in the emergence of damaging responses to self antigens. The immune system and its regulatory mechanisms are not simple, as one would expect of a homoeostatic process that also has the ability to expand enormously when challenged and to contract rapidly when threats pass. These processes that avoid damaging anti-self B cells are much more complicated than that envisaged in standard two signal models. Simple signals through the B cell antigen-receptor probably encourage B cell survival and receptivity, while other signals (costimulatory or coinhibitory) promote B cell stimulation or non-stimulation/inactivation.