Hyperinflammatory disease and vasculitis-associated autoimmune disease pathogenesis by novel virulent pathogens inducing lymphocyte exhaustion and/or suppression

Hyperinflammatory diseases and several autoimmune diseases are linked to pathogen infections, but the pathogenesis remains elusive. A hyperinflammatory and autoimmune disease pathogenesis theory should explain how several pathogens can cause numerous distinct hyperinflammatory and autoimmune diseases

Virulent pathogen infections can cause lymphocyte exhaustion and/or suppression [1]. Some virulent pathogen infections can cause multiple lymphocyte exhaustions and/or suppressions of immune cells, including natural killer NK-cells and thymic T-cells [1]. Lymphocyte suppression has several causes. Known causes include tissue hypoxia (reduced oxygen levels); neuroendocrine activations (e.g., glucocorticoids); hypercoagulable blood states (e.g., increased tissue factor, fibrin, thrombin and platelet activation); pro-inflammatory prostaglandins (e.g., prostaglandin E2); interleukin-6 (IL-6), anti-inflammatory phase factors including interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1), regulatory T-cells or myeloid-derived suppressor cells (MDSCs) [2, 3].

T-cell exhaustion, bone marrow B-cell and NK-cell exhaustion include inhibited functionalities and proliferation caused by continuous antigen stimulation resulting from chronic infections or cancers [3]. Lymphocyte exhaustion over time can become almost irreversible, unlike suppression, which can be reversible [3].

A theory for hyperinflammatory disease and vasculitis-associated autoimmune disease pathogenesis follows. This involves exhaustion and/or suppression of lymphocytes, including NK-cells, T-cells and/or B-cells, where lymphocyte exhaustion and/or suppression can potentially be involved in up to three distinct pathogenesis steps. This theory applies to individuals having transient or permanent immuno-deficiencies (e.g., complement deficiencies) in their antigen–antibody immune complex phagocytosis abilities [4].

Very high titers of antigen–antibody immune complexes can result from a relatively quick pathogen-induced lymphocyte exhaustion and/or suppression that enables high replication rates for pathogens and their antigens [4]. This is the first lymphocyte exhaustion and/or suppression involvement, involving cytolytic NK-cells and/or T-cells targeting pathogen-infected cells.

A quick lymphocyte exhaustion and/or suppression is important in the next step, due to the time follicular helper CD4⁺ T-cells require to assist B-cells in developing more effective antibodies by affinity maturation and isotype switching to target novel pathogen antigens produced from a first-time virulent pathogen infection [5]. This is the second potential lymphocyte exhaustion and/or suppression involvement, involving follicular helper CD4⁺ T-cells. Either this involvement, or alternatively impaired B-cells, can result in ineffective antibodies, ultimately creating very high titers of antigen–antibody immune complexes. The alternative path without follicular helper CD4+ T-cell exhaustion could involve B-cells, impaired from a previous B-cell pathogen infection (e.g., a herpesvirus) or another cause of B-cell dysfunction, secreting ineffective antibodies [3].

Very high titers of antigen–antibody immune complexes will initiate a Type III hypersensitivity immune reaction, resulting in increased populations of activated T-cells and other activated immune cells which will secrete a variety of proteinases that express or expose a variety of autoantigens while cleaving host proteins [4]. However, if immunoregulatory NK-cells and/or regulatory T-cells are also exhausted and/or suppressed in their ability to reduce populations of activated T-cells and other activated immune cells, the proteinase-created autoantigens will continue to autoantigen-activate T-cells and other immune cells to release more proteinases to autoantigen-activate more T-cells and other immune cells [6, 7]. This is the third potential lymphocyte exhaustion and/or suppression involvement, involving immunoregulatory NK-cells and/or regulatory T-cells.

This theory can explain how multiple pathogens cause several specific inflammatory diseases. For example, resulting blood vessel endothelial cell inflammation can exhibit vasculitis [4]. If the individual’s immune system impairment is temporary, a transient hyperinflammatory disease occurs; if not, a chronic vasculitis-associated autoimmune disease (e.g., systemic lupus erthematosus, rheumatoid arthritis, or other disease) occurs. Homeostasis restoration may require regulatory T-cells, immunoregulatory NK-cells, MDSCs, proteinase inhibitors and/or other agents.

Ineffective antibodies result from impaired follicular helper CD4⁺ T-cells, located in lymph node and spleen germinal centers [5]. Follicular helper CD4⁺ T-cells are crucial for antibody affinity maturation, isotype switching, memory B-cell creation and B-cell differentiation into immunoglobulin (antibody) secreting plasma cells [5]. Follicular helper CD4⁺ T-cell exhaustion is possible and would impair effective antibody production [5]. Consequently, novel infections by a virulent pathogen (e.g., SARS-CoV-2 virus) will be difficult to suppress due to quantitatively and/or qualitatively inadequate immunoglobulins (antibodies) secreted by B-cells and plasma cells [5].

Recent observations of SARS-CoV-2 virus infections provide supportive evidence. Severe COVID-19 patients exhibit ineffective B-cells, and these patients have higher population fractions of less-developed membrane-bound IgM immunoglobulin on B-cells, compared to higher population fractions of more developed membrane-bound IgG immunoglobulins on B-cells seen in control patients [10]. These immunoglobulin isotype differences suggest T-cell exhaustion or suppression of germinal center follicular helper CD4⁺ T-cells impaired B-cell isotype switching and somatic hypermutation affinity maturation of immunoglobulins targeting the SARS-CoV-2 virus [5, 10].

The SARS-CoV-2 virus ability to induce both NK-cell exhaustion and T-cell exhaustion impairs the immune system’s capability to inhibit replication of SARS-CoV-2 virus [1], and increased SARS-CoV-2 virus replication will cause higher antigen and antigen–antibody immune complex titers [10].

COVID-19-associated hyperinflammatory disease multisystem inflammatory syndrome (MIS) provides evidence of concurrent T-cell exhaustion and immunoregulatory NK-cell exhaustion [8, 9]. Immunoregulatory NK-cell and autoantigen-activated T-cell involvements in autoimmune diseases are also documented [6, 7].

In conclusion, a theory is proposed involving individuals having transiently or permanently induced immuno-deficiencies in phagocytizing high titers of antigen–antibody immune complexes. Very high titers of antigen–antibody immune complexes can result from pathogen-induced lymphocyte exhaustion and/or suppression, enabling high pathogen and antigen replication rates. A quick-paced exhaustion and/or suppression is probably involved, quicker than the necessary time required for follicular helper CD4⁺ T-cells to assist B-cells in developing and secreting more effective antibodies by affinity maturation and isotype switching to bind antigens produced from a first-time pathogen infection. The result is very high titers of antigen–antibody immune complexes. Very high titers of antigen–antibody immune complexes will initiate a Type III hypersensitivity immune reaction, producing increased populations of activated T-cells and other activated immune cells, releasing proteinases that express or expose various autoantigens from cleaving host proteins. However, if immunoregulatory NK-cells and/or regulatory T-cells are also exhausted and/or suppressed, they will not control activated T-cells and other activated immune cell populations, and autoantigens will continue to autoantigen-activate more T-cells and other immune cells that release more proteinases that autoantigen-activate more T-cells and other immune cells. If an individual’s immune system impairment is temporary, a transient hyperinflammatory disease occurs. If homeostasis cannot be restored, a chronic autoimmune disease occurs. Hyperinflammatory diseases and/or vasculitis-associated autoimmune diseases can result from multiple lymphocyte exhaustion and/or suppression induced by pathogen infections, also including impairment of immunoregulatory lymphocytes or other agents that would otherwise control or prevent these diseases.

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