What is the main function of the human immune system

Publisher Summary

The immune system functions on two levels: innate and adaptive. Innate immunity is more primitive and forms a rapid early warning system for global immunity. It evolved to protect single and multicellular organisms from danger. The innate immune system depends on a network of “danger” receptors, called pattern recognition receptors (PRRs), which are germ line encoded and recognize many different danger signals. Adaptive immunity develops slowly but delivers precise antigen-specific responses with immunological memory. The innate and adaptive systems are asymmetrically interdependent. The two stages of preeclampsia involve two different immune interfaces with different interactions between different types of trophoblast: invasive (Interface 1) and syncytiotrophoblast (Interface 2). Recognition of the foreign fetus can only occur at Interface 1, and may involve T-regs or a very pleiomorphic interaction between uNK cells and HLA-C on extravillous trophoblast. Pregnancy imposes a substantial systemic inflammatory stress on all gravidas in the second half of pregnancy. This generates many features that are considered to be physiological responses to pregnancy but are best considered as components of an acute phase response, for example, reduced plasma albumin, hypercoagulability, or leukocytosis. Preeclampsia occurs when this response is increased to the point of decompensation.

22.5.5.9 HIV-Specific Cytotoxic T Lymphocytes

Passive restoration of the immune system function by using an infected individual’s own cells is another technique of gene therapies for containing HIV infection. This involves an ex vivo expansion of either CD4 or CD8 lymphocytes, which are then reinfused into the HIV-1-infected individual. In this context, CD8 cells have been mainly used as adoptive cell therapy for HIV-1 infection. Since early in the infection there is a rise in HIV-specific CD8 cells, this correlates well with the improvement of viremia. Thus MHC class 1–restricted CD8 cells play a role in containing infection during the acute phase of infection (Dwivedi et al., 2013a,b).

Abstract

Migration is essential for immune system function, from the establishment of the hematopoietic system in the bone marrow through to the capture and killing of invading pathogens. This reliance on migration is demonstrated by the existence of a subset of inherited immunodeficiencies that are a result of mutations that impact on migratory processes. Much of our understanding of the importance of migration in the immune response comes from the study of these immunodeficiencies. Wiskott–Aldrich syndrome is the first described and best studied migratory immunodeficiency, and this article will focus on this disorder, and its wide ranging impact on immune function. We will also give an overview of other migration defects that lead to immunodeficiency, including their genetic, biochemical, and cell biological basis.

3.1 Underlying mechanisms of exercise benefits

Physical activity improves immune system function and decreases neuroinflammatory response (Kohut et al., 2006; Skalicky & Viidik, 1999). How exercise affects microglial proliferation appears dependent on the duration and timing of exercise, with some studies reporting increased microglial proliferation in response to wheel running (Barton, Baker, & Leasure, 2017; Ehninger & Kempermann, 2003) and others showing the opposite effect (Ehninger et al., 2011; West et al., 2019). Regardless of the number of microglia, however, exercise has been consistently shown to decrease microglial activation (Barton, Baker, & Leasure, 2017; He et al., 2017; Jiang et al., 2017; Kohman, Bhattacharya, Wojcik, & Rhodes, 2013; West et al., 2019) and increase the release of trophic factors by microglia (Kohman, DeYoung, Bhattacharya, Peterson, & Rhodes, 2012). Exercise also increases antioxidant activity (Alessio et al., 2005), which may contribute to exercise's neuroprotective effect against oxidative stress (Brocardo et al., 2012; Gerecke, Kolobova, Allen, & Fawer, 2013; Lu et al., 2017; Somani & Husain, 1997). Although exercise activates biological systems related to the stress response, since it is a controllable and rewarding stressor, exercise may serve to help regulate HPA axis functioning to other stressors (Stranahan, Lee, & Mattson, 2008).

Improved trophic support is one of the most likely mechanisms for the beneficial effects of physical activity on the brain (Phillips, Baktir, Srivatsan, & Salehi, 2014). Exercise increases trophic factors in multiple brain regions (Carro, Trejo, Busiguina, & Torres-Aleman, 2001; Cotman et al., 2007; Ding, Vaynman, Souda, Whitelegge, & Gomez-Pinilla, 2006; Ding, Ying, & Gomez-Pinilla, 2011; Gao et al., 2014; Neeper, Gomez-Pinilla, Choi, & Cotman, 1995; Neeper, Gomez-Pinilla, Choi, & Cotman, 1996; Trejo, Carro, & Torres-Aleman, 2001; Yu, Ma, Ma, & Tao, 2014). Brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial-derived growth factor (VEGF) are some of the trophic factors which are upregulated in response to exercise, and also appear to have important roles in the positive neural effects of exercise (Farmer et al., 2004; Trejo et al., 2001; Yu et al., 2014). When activity of BDNF and IGF-1 are blocked, exercise-induced neurogenesis does not occur (Ding, Vaynman, Akhavan, Ying, & Gomez-Pinilla, 2006; Trejo et al., 2001; Vaynman et al., 2004). In addition to increased neurogenesis, exercise also promotes neural health and survival via the increased release of growth factors (Cotman et al., 2007). These trophic factors act synergistically to control plasticity, cellular function and maintain overall neural health, and are therefore likely responsible for many of the benefits resulting from exercise.

Conclusions

In summary, the immune system functions to protect the body from bacterial and viral infections as well as other foreign material such as environmental contaminants. Both the innate and adaptive functions of the immune system are required for the protection from and removal of new and recurrent exposures to potentially harmful xenobiotic materials. The activation of leukocytes followed by the production of protective molecules like cytokines, chemokines, and antibodies help with protection against exposures to foreign substances. These molecules function to protect the body; however they are destructive in nature and when over produced or left to persist, they can extensively damage healthy tissue. Under normal conditions, the immune system is highly specific and tightly regulated. However, when exposed to excessive insult, as with chemical exposures, or in disease states, such as autoimmunity, the regulatory mechanisms are dysfunctional resulting in an immune system that can be damaging to the host. This disruption of immune function places the individual at greater risk of health complications associated with subsequent environmental exposures, and/or bacterial and viral infections. Elucidating the molecular modifications associated with environmental exposures that mediate immune dysregulation will help to identify biomarkers of exposure and disease. This in turn will ultimately assist in identifying, treating, and preventing future disease associated with exposures to these environmental contaminants.

Why do we need it?

Progress in understanding how the immune system functions has relied a great deal upon ‘readout systems’ that require the introduction of antigen at one point in time, and quantitation of ‘total response’ (e.g. antibody levels) some time later. A large antibody response could have come from a few starting lymphocytes each responsible for high-level production, or it could have come from many lymphocytes producing far less. To fully understand the biology of the cellular events that follow antigen stimulation, one would like to know how many parent (or precursor) lymphocytes in a given starting population were triggered to produce the clones that eventually made the antibody. In other words, one would like to know the frequency of the precursor cells that exist within the starting population of lymphocytes, and the proportion of them that may be used in any response.

There is no simple (e.g. visual) way of being able to identify which of the cells in a large population will go on to produce an active clone. Antigen-specific precursors are rare and morphologically indistinguishable from the silent majority of resting lymphocytes. Limiting dilution analysis (LDA) allows the calculation of precursor frequencies as a retrospective process based on the measurement of the number of active clones generated from a given population of cells. As each active clone is derived from one precursor, then retrospectively one can estimate the frequency of precursor cells that gave rise to those clones.

Estimation of the precursor frequency can indeed be an end in itself, e.g. if one wished to determine the frequency of alloreactive cells that the bone marrow of a potential donor might have toward the graft recipient. Too high a frequency might reasonably predict aggressive graft-versus-host disease and would therefore be unacceptable.

The realization that there was a need for this sort of measurement in immunology, as well as the development of suitable technology to make it possible, led to the first important paper on the subject by Lefkovits in 1972, from which LDA has developed as an extremely powerful tool in immunology.

IMMUNE DEFICIENCY AND CHRONIC/RECURRENT BRONCHITIS

Children with selective deficiencies in immune system function have increased susceptibility to respiratory infections and to delayed resolution of symptoms.34 Chronic recurrent bronchitis has been reported in selective immunoglobulin A (IgA) deficiency, in IgA deficiency associated with IgG subclass deficiency (especially IgG2), and in combined deficiency of IgG2 and IgG4 in the presence of normal total IgG and IgA. Common variable IgG deficiency, a disorder of B-lymphocyte function associated with inadequate production of immunoglobulins, has also been associated with chronic/recurrent pulmonary disease including tracheobronchitis. Children who are unable to respond to the capsular polysaccharide have been shown to have an increased frequency of respiratory tract infections (pneumonia, sinusitis, and otitis). Similarly, children who cannot respond to the polysaccharide antigen contained in the wall of certain bacteria have also been reported to develop recurrent episodes of bronchitis. The measurement of the specific response to the H. influenzae type b capsular polysaccharide vaccine or to the subtypes of the pneumococcal vaccine can be used to identify these children. Bronchitis obliterans has been reported as a complication of immune deficiency in children.35

Recognition of these immune deficiencies can have important therapeutic implications. More aggressive antibiotic therapy coupled with antibody replacement therapy is indicated to control symptoms.

Innate immunity defects

The innate arm of the human immune system functions responds to the initial stages of infection, particularly after the compromise of the skin and mucosal barriers. The cellular components of the innate immune system include macrophages, natural killer cells, CD8+ T cells, Th27 CD4+ T cells, and neutrophils. Innate immune response is nonspecific and requires no immune memory, differentiating it from the adaptive arm of the immune system [54]. This section highlights two categories of innate immune defects and their laboratory basis.

Chronic mucocutaneous candidiasis (CMC). Mutations in several genes lead to a presentation of infections of the nails, skin, and mucus membranes with Candida and dermatophytic fungi. This group of diseases arises from defects in the function of the innate immune system to fight infection to these common environmental fungi. Genes involved include STAT1, IL17RA, IL17RC, IL17F, TRAF3IP2, and ACT1. Mutations lead to defects in Th27 CD4+ T cells that produce IL-17 which is key to mucosal immunity [55,56]. In addition to the chronic fungal infections of the skin, nails, and mucous membranes, people with STAT1 gain of function mutations also develop viral infections, bacterial infections, and autoimmunity. The importance of the IL-17 cytokine in chronic mucocutaneous candidiasis is highlighted by the high frequency of autoantibodies against IL-17 and related IL-22 in patients with autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy (APECED) syndrome in which candidiasis is seen. The autoimmune effects of APECED are due to mutations in AIRE, a gene that codes for regulators of self-antigen.

Treatment of CMC syndromes focuses on treating symptomatic infections and underlying defects. Ruxolitinib, a JAK1/2 inhibitor has shown efficacy in improving CMC in patients with STAT1 gain of function (GOF) mutations in one case series [57]. Patients with Candida infections are commonly treated with the antifungal fluconazole, but resistance has been documented in some cases.

Laboratory features of CMC depend on the mutation type, but the diagnosis depends on the isolation of Candida species or dermatophyte fungi from cultures of mucocutaneous lesions. Other lab testing includes abnormal IL-17 pathway activation. Patients with STAT1 GOF mutations demonstrate decreased IL-17 in Candida stimulated peripheral mononuclear cells (PBMCs), decreased IFN-γ in IL-12 stimulated PBMCs [58], and elevated STAT1 protein [59]. Patients with ACT1 mutations demonstrate low IL-5 expression after stimulation with IL-2 and IL-17E by ELISA [60].

Mendelian susceptibility to mycobacterial disease. Primarily related to defects in the IFN-γ pathway, one class of innate immune defects features special susceptibility to mycobacterial disease. The genes involved include IFNGR1, IFNGR2, IL12RB1, IL12B, STAT1, CYBB, RORc, IRF8, ISR15, and TYK2 [84]. The primary presenting clinical manifestations of patients with these mutations are mycobacterial infection but can also include other intracellular organisms including Salmonella, Listeria, and viruses, such as human herpesvirus 8, herpes simplex virus, Cytomegalovirus, and varicella-zoster virus [61]. Treatment of patients with mycobacterial disease depends on the species of mycobacteria. Susceptibilities vary widely across and within mycobacterial species. Multiple antibiotics are required to clear infections typically. Depending on the genetic defect, IFN-γ therapy can help to clear infections. Long-term antibiotic courses are common. Hematopoietic progenitor stem cell transplantation has been attempted but has not been very successful to date.

Patients with IFN-γ receptor deficiency will have a markedly elevated IFN-γ. Flow cytometry of NK cells and T cells for IL-12 receptor can be diagnostic for IL-12 receptor deficiency. Functional studies to evaluate the IFN-γ function of cells may be required to diagnose other defects. Phosphorylation of STAT1 protein can be evaluated by electrophoretic mobility shift assay or flow cytometry for intracellular p-STAT1. Other tests include measurement of cytokines after stimulation of PBMCs, EBV-transformed lymphoblastoid cell lines, or SV40 fibroblasts [62]. These tests are very specialized and not available in commercial laboratories.

Immune cells

It is commonly accepted that the immune system functions as a major defense against cancer cells and that different immune cell populations can have either pro- or anticancer effects. In metastasis, evidence suggests that antitumoral or protumoral immune microenvironments may be dependent on the local cytokine milieu, presence of accessory stromal cells, tumor-specific interactions, and subsets of immune cells present. The bone presents a unique environment that, compared with the peripheral circulation, is immune-privileged containing a low abundance of cytotoxic T and natural killer (NK) cells and a high proportion of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs) [63]. It is believed that this immune-suppressive environment is important for the maintenance of the hematopoietic stem cell niche; however, reduced immunity also has major implications for the development of tumor growth in this site. Cytotoxic T cells release TNFα and interferon γ (IFNγ) to eliminate tumor cells and NK cells kill tumor cells through granzyme B and perforin-induced apoptosis making these cells primary mediators of tumor cell clearance [64]; therefore low numbers of these immune cell populations, in bone, produce a tumor-promoting environment. Conversely, other types that are increased in bone, including Treg, helper T cells, suppressive dendritic cells, and MDSCs, actively promote tumor growth and metastasis [63,65]: Tregs promote tumor cell metastasis to bone through CXCR4/CXCL12 signaling and/or the RANK/RANKL axis [66,67]; whereas dendritic cells suppress the cytotoxic capacity of CD8+ T cells via production of arginase I, nitric oxide, TGFβ, and IL-10 to promote tumor progression [68–70]. MDSCs also suppress CD8+ cells via the same mechanisms used by dendritic cells in addition to releasing cytokines including IL-6, VEGF, basic fibroblast growth factor, and matrix metalloproteinase-9 to promote cancer progression and bone metastasis [71–73]. Macrophages and neutrophils also influence tumor growth in bone. In response to immunosuppressive cytokines secreted by tumor cells, the M1 macrophages and N1 neutrophils become polarized to tumor-associated M2 macrophages and N2 neutrophils which have tumor-promoting properties [70]. In the bone tumor–associated M2 macrophages secrete high levels of IL-10 and TGFβ to decrease activation of CD4+ and CD8+ T cells [74,75]. Additionally, tumor-associated N2 neutrophils release CXCR4, VEGF, and MMP9 to promote bone metastasis [76,77]. Taken together, these data suggest that immune regulation in bone works in favor of tumor growth rather than suppression and may, in part, explain why this is a common site for metastases.

In addition to directly influencing the growth of tumors in bone, immune cells also regulate bone turnover mainly through OPG/RANKL/RANK signaling. CD4+ T cells can release cytokines such as IL-6, IL-11, IL-15, and TNFα contributing to enhanced osteoclastogenesis and the formation of osteolytic lesions [73,78]. Once activated these CD4+ T cells can further increase osteoclast activity and bone destruction through the release of OPG-L [79]. As well as secreting proosteolytic factors evidence suggests that activated CD4+ cells can also reduce osteoclast activity through the production of interferon Gamma (IFN Gamma) [80,81]. It therefore seems likely that the balance between the bone-destroying protumorigenic and the bone-protective antitumor effects of immune cells may play a significant role in the likelihood of metastases forming in this site.

Interactions between immune cells and osteoblasts are more complex, both B cells and macrophages interact with osteoblasts to regulate immunity and bone turnover. Osteoblasts are essential for the regulation and differentiation of all stages of B cell development; therefore any tumor cell interactions that lead to reduced osteoblast numbers has a knock-on effect of reducing mature B cells required for tumor cell killing [82]. Macrophages, on the other hand, regulate osteoblast differentiation and mineralization of the bone matrix [82]. These data indicate a key role for immune cells in regulating the endosteal niche, thus, determining the fate of tumor cells disseminated in this site.