Understanding the Immune System's Intricate Balance: Activation, Tolerance, and Self-Protection

Abstract

Understanding the mechanisms of immune activation and deactivation is paramount. A host must initiate effective immunity against pathogenic infections while avoiding triggering immunity against self-antigens, which can lead to detrimental autoimmune disorders. Host immunological pathways can be categorized as Immunoglobulin (Ig)G-dominant eradicable immune reactions and IgA-dominant tolerable immune reactions. Eradicable immune reactions include Th1, Th2, Th22, and Thαβ immune responses against four different types of pathogens. Tolerable immune reactions include Th1-like, Th9, Th17, and Th3 immune responses against four different types of pathogens. Here, we try to determine the mechanisms of activation and deactivation of host immune reactions. The spleen and liver play contrasting roles in mediating immune responses: the spleen is primarily involved in immune activation, whereas the liver is responsible for immune deactivation. Similarly, the sympathetic and parasympathetic nervous systems have opposing functions in immune modulation, with the sympathetic system promoting pro-inflammatory responses and the parasympathetic system facilitating anti-inflammatory processes. Furthermore, adrenocorticotropic hormone (ACTH) and glucocorticosteroids exhibit contrasting effects on immune regulation: ACTH is involved in activating adaptive immunity while inhibiting innate immunity, whereas glucocorticosteroids activate natural IgM antibody associated with innate immunity while inhibiting adaptive immunity. Heat shock proteins, particularly molecular chaperones induced by fever, play pivotal roles in immune activation. Conversely, IgD B cells and gamma/delta T cells contribute to immune deactivation through mechanisms such as clonal anergy. Understanding these mechanisms provides insights into immunological pathways, aiding in the better management of infectious diseases and autoimmune disorders.

Keywords: ACTH; IgD; gamma/delta T cells; parasympathetic; steroid; sympathetic.

Figure 1

The immune activation and tolerance mechanisms in the liver and spleen. The spleen is responsible for generating B cell antibodies, including IgG and IgM, and the liver is responsible for generating gamma/delta T cells with clonal anergy. Heme production from hemoglobin inside the spleen provides an immune activation environment in the spleen. The spleen HO-1 enzyme generates CO and bilirubin transported via the splenic vein to the liver to help immune tolerance in the liver.

Figure 2

The relationship between the autonomic nerve system and inflammation and anti-inflammation. The sympathetic nerve will enhance intracellular cAMP to activate protein kinase A to induce inflammation. Norepinephrine can promote THαβ immunity, and epinephrine can promote TH17/22 immunity. The parasympathetic nerve will enhance intracellular cGMP to activate protein kinase G to suppress inflammation. Acetylcholine can suppress TH1, TH2, TH17/22, and THαβ immunities and promote TGFβ activity.

Figure 3

The HPA axis and immunity. The HPA axis contains the CRH -> ACTH -> glucocorticoid pathway. There is also negative feedback. ACTH can inhibit CRH, and glucocorticoids can inhibit CRH as well as ACTH. ACTH can suppress innate immunity and stimulate adaptive immunity by promoting lymphocyte activity. Glucocorticoids can suppress adaptive immunity and stimulate innate immunity by promoting T cell-independent IgM antibody.

Figure 4

(a) HSP70 and HSP60/HSP10 complex; (b) HSP70/40 and HSP90/SR; (c) steroid receptor. HSP70 can help generate a mature HSP60/HSP10 complex. HSP40, HSP70, HSP90, and SHR can also form an intermediate complex. Then, a mature complex with HSP90 and SHR can be formed to inhibit the activity of SHR. When steroid binds to SHR in the HSP90/SHR complex, the SHR will be released from the HSP90/SHR complex to bind to DNA for HRE transactivation and NFkB/AP1 transrepression.

Figure 5

Antibody-dependent enhancement. The IgG3 antibody is mainly against intracellular bacteria. When a virus infection induces IgG3 antibody generation, it can bind to the virus and the Fc receptor to be ingested by macrophages. Macrophages cannot digest virus particles but instead produce a lot of pro-inflammatory cytokines to induce a cytokine storm. This is the mechanism of antibody-dependent enhancement.

Figure 6

(a) Gamma/delta T cells and IgD B cells; (b) classification of gamma/delta T cells. The immune deactivation is related to the clonal anergy of gamma/delta T cells and to the clonal anergy of IgD B cells. The immune activation is related to the IgM B cells and subsequent IgG/IgE/IgA B cells and to the alpha/beta T cells. Gamma/delta T cells have three subtypes that exist in the intestine, blood, and liver to mediate immune tolerance.