Immunity 

Immunity can be defined as a complex biological system endowed with the capacity to recognize and tolerate whatever belongs to the self, to recognize and reject what is foreign (non-self) 

Immunity

Introduction

Immunity is an extensive topic, worthy of an encyclopedia of its own. Here we cannot summarize the field in detail but will identify key concepts. These concepts include (1) the difference between innate and acquired immunity and how they relate to each other; (2) the notions of specificity and immune memory; (3) the sometimes antagonistic concepts of self and danger; and (4) the mutually defined ideas of an antigen and its receptor. This article will arm the microbiologist not with a storehouse of information, the classic goal of an encyclopedia, but with a fundament of understanding with which to read the larger literature of immunity.

The word ‘immunity’ derives from the Latin communitas, the legal status of Roman city-states granted immunity from paying tributes to Rome or to individuals freed from municipal duties; the root munis referring to change and (ex)changeable goods. This is the direct origin of the legal meaning of ‘immunity from prosecution, but, in the first century, Lucan (De Bello Civile) had already used the word metaphorically to describe the Psylli of North Africa as immune to the bites of venomous snakes. Biological immunity can refer to constitutive physical innate mechanisms, such as the physical protection afforded against infection by skin, the activity of natural killer (NK) cells against virus-infected cells, or the natural resistance of mice to diphtheria toxin because of the absence of a receptor for that toxin. Immunity can also be innate but inducible, as in the antiviral state induced by exposure to double-stranded RNA (dsRNA). Finally, immunity to specific microbes can be acquired during the lifetime of the individual by infection or vaccination.

The origins of immunology as science are lost in antiquity but have always been fundamentally connected with microbiology. It was certainly known before the beginning of the Common Era that survivors of certain plagues (perhaps smallpox) were immune to its recurrence. Observations such as these were rendered uncertain by imprecise diagnoses of the illness but advanced sufficiently so that by the end of the first millennium, Common Era, Chinese and Hindu healers were aware of the efficacy of the homeopathic practice of insufflation, in which powdered scabs of the afflicted were blown through straws into the lungs of healthy individuals. 

This observation drew these ancient doctors to a fundamental insight on acquired immunity – some property of the diseased could induce long-standing and specific protection in naive individuals. Centuries of observations and reconceptualizations about the specificity of this protection led to Fracastoro’s fourteenth-century germ theory of infectious disease, which held that infectious diseases were caused by disease-specific agents. This core concept was dealt a minor blow in the late 1700s when Jenner found that vaccination with cowpox protected against the different though closely related disease smallpox. However, the successes of both variolation and vaccination spurred the deliberate experiments of Pasteur in the following century to develop attenuated vaccines and a modern version of the Specific Germ Theory of infectious disease. The modern concepts of acquired immunity maintain that induced protection is specific for each infectious agent, but recognizes specificity at the level of molecules rather than microbes, which allows cross-reactivity and self-reactivity (autoimmunity).

Immunity

The immune system protects us from invading pathogenic microorganisms and cancer. Immunity – the state of protection from infectious disease – has both a less specific or INNATE and a more specific or ADAPTIVE component.

Innate Immunity

This provides the first line of defense against infection. It is a rapid response (minutes); it is not specific to a particular pathogen. It has no memory and does not confer long-lasting immunity to the host. It has 4 main components and is found in all classes of plant and animal life.

Adaptive Immunity
This provides a specific immune response directed at an invading pathogen. Following exposure to a foreign organism, there is an initial EFFECTOR RESPONSE that eliminates or neutralizes a pathogen. Later re-exposure to the same foreign organism induces a MEMORY RESPONSE with a more rapid immune reaction that eliminates the pathogen and prevents disease. This response is found only in vertebrates.
It has been known from historical times that a person who has recovered from an infectious disease, e.g. smallpox, is most unlikely to suffer from it again – even when exposed maximally – although he would remain susceptible to other infections.

That is, during the recovery period he has acquired specific immunity to smallpox but not to other unrelated infections.
Note: This immunity may extend to related infections: the use of the immunity against smallpox conferred by worldwide vaccination with cowpox (pioneered by Jenner in the 18th century) has completely eliminated smallpox throughout the world.

The Immunology of Human Immunodeficiency Virus Infection

Role of Immune Activation in the Pathogenesis of HIV Infection
The end result of HIV infection is profound immunodeficiency; however, paradoxically, HIV infection is associated with hyperactivation of the immune system throughout most of the course of the disease. HIV subverts the immune system by inducing immune activation, using this milieu toward its own replicative advantage, and causing widespread damage to the immune system. 

Whereas it is well accepted that the replicative cycle of HIV infection is most efficiently achieved in activated cells, most of the damage caused by HIV is not the result of direct infection of CD4+ T cells but, rather, the widespread bystander activation, dysregulation, and cell death of CD4+ T cells and other cells of the immune system. In this regard, numerous studies have demonstrated that the level of CD8+ T-cell activation, as measured through the expression of CD38 and HLA-DR, is a better correlate of HIV disease progression than HIV viremia.

4 More recently, alterations in expression and secretion of factors or biomarkers, especially those associated with the myeloid lineage such as soluble CD14 and D-dimer, among others, have also been proposed as indicators of immune activation induced by both active viral replication and by the residual effects of viremia in individuals receiving effective ART. The persistence of immune activation in individuals receiving ART is thought to explain, at least in part, their increased risk of comorbidities, such as cardiovascular and liver diseases, type 2 diabetes, osteoporosis, and malignancies.

About T cells, and to lesser extent B cells and NK cells, the evidence for HIV-induced immune activation is severalfold. There is a high frequency of cells expressing markers of activation and cell cycling that is accompanied by homeostatic dysregulation and cell death during ongoing HIV replication. Many of these manifestations are attenuated or reversed by effective ART. 

One of the most widely accepted indirect pieces of evidence that immune activation plays a major role in HIV immunopathogenesis is the nonpathogenic outcome of SIV infection in its natural host. In the case of naturally SIV-infected sooty mangabeys, high levels of SIV viremia occur in the absence of generalized immune activation and progressive CD4+ T-cell depletion. 

In further contrast to HIV infection, which almost invariably leads to AIDS if left untreated, SIV infection in natural hosts rarely leads to disease progression. Over the years, the differences between pathogenic HIV infection in humans and nonpathogenic SIV infection in nonhuman primates, such as sooty mangabeys, have been extensively investigated. The most consistent feature of these comparisons remains the lack of generalized immune activation in natural SIV infection, with muting of the innate immune response, including systemic inflammation and a strong type I IFN response after the acute phase, being the most important difference observed between naturally controlled SIV and uncontrolled HIV infections.

The Epidemiology of Plasmodium vivax

TBI appears to depend on the malaria transmission intensity, suggesting that the generation of TBI requires prolonged exposure to multiple malaria inoculations (Bousema et al., 2010; Premawansa et al., 1994). TBI also correlates with the period of exposure to gametocytes and the number of gametocytes developed during the infections; sera of individuals with high Ab concentrations are more efficient at blocking parasite transmission to the mosquito (Boudin et al., 2004; Bousema et al., 2011). Sera of humans exposed to P. falciparum contains IgG Abs that recognize sexual-stage antigens on the surface of gametocytes and gametes. Pfs230 and Pfs48/45 were identified as antigens responsible for the TBI (Carter, 2001; Healer et al., 1999; Roeffen et al., 1994). The levels of Abs against Pfs230 and Pfs48/45 could be boosted by exposure to gametocytes in further infections (Bousema et al., 2010). Recently, Sutherland has summarised the efforts to identify novel sexual-stage antigens conferring TBI against P. falciparum (Sutherland, 2009).

Staphylococcus☆

Immunity to staphylococcal infections is poorly understood. Normal healthy humans have a high degree of innate resistance to invasive infections. Experimental infections are difficult to establish in animals and require large inocula containing millions of organisms. In humans, the organism can colonize mucosal and epidermal surfaces with little resistance, and as long as they remain intact, these barriers are the main source of natural immunity to infection. After the invasion, however, phagocytosis by polymorphonuclear leukocytes is the main humoral defense. Because of repeated exposure to S. aureus and S. epidermidis in natural settings, antibodies to various components of the cell and its products (both cell surface and soluble) are prevalent in animals. Nevertheless, except for toxic shock syndrome where the antibody is an important factor in immunity, serological studies have not successfully related immunity and antibody titer. Moreover, prior infection fails to elicit immunity to reinfection. Despite these drawbacks, vaccine research is being pursued strongly. Although there is currently no vaccine that stimulates active immunity in humans, a vaccine based on fibronectin-binding protein has been shown to confer protective immunity against mastitis in cattle. Among the vaccines being studied for use in humans, the most promising is a polysaccharide conjugate vaccine that was given Fast Track Status by the FDA in 2004 for the prevention of bacteremia in certain at-risk patient populations; however, the vaccine failed to reduce the incidence of S. aureus infections when used in clinical trials.

Ontogeny of Immune Development and Its Relationship to Allergic Diseases and Asthma

Impact of Environmental Exposures on Immune Maturation and Risk for Allergic Disease

There is a growing body of evidence emphasizing the environmental impact on immune maturation, with the strongest data found in the allergy literature. The most critical periods for immune maturation and allergen sensitization occur simultaneously, beginning in utero and during the first 2 years of life. As mentioned previously, the hygiene hypothesis posits that environmental and exogenous exposures modulate the maturing immune system and can direct the development of allergic immune responses.

Epidemiologic studies from several world regions demonstrate that children raised on farms are less likely to develop allergic diseases, including asthma than other children raised in the same rural community but not on farms. Early life farm exposure is associated with differences in immune phenotypes and function. Neonates born to mothers on European farms were found to have increased proinflammatory (e.g., IL-6 and TNF-α) cord blood cytokine responses compared with neonates born to nonfarming mothers. An independent study, from a smaller sample size, demonstrated increased Treg cell numbers and function in cord blood from neonates born into farming environments. These data suggest that environmental exposures can modulate the maturing immune system and result in clinically significant differences, measured in this case by the development of allergic sensitization.

Most work in this area has focused on bacterial exposures, particularly in the airborne environment. Early studies focused on the bacterial component LPS proposed an “endotoxin switch” model with a continuum of varied outcomes depending on timing, genetics, and environmental exposure loads. A study comparing the synergistic effect of LPS on TCR cross-linking in neonates and adults found that cord blood mononuclear cells deviated away from Th2 cytokine production toward Th1 cytokine production, whereas adult peripheral blood mononuclear cells were unaffected. Early life farm exposure, including prenatal exposure, is associated with increased mRNA expression of LPS-responsive innate immune receptors (TLR2, TLR4, CD14) in blood mononuclear cells. Proposed explanations for this endotoxin protection against Th2 inflammation include alterations in Th2/Th1 balance, modulation of Treg cells, and antiinflammatory effects mediated by the innate immune system. In fact, endotoxin levels are reported to be elevated in farm households compared with rural nonfarm households.

With the advent of improved technologies to better define environmental and individual microbiota, numerous studies have expanded our knowledge of the complexities of the microbial world, the stability of personal microbiomes, and the critical windows of exposure in modulating immune maturation.

Infections in Older Adults

Waning Immunity With Age (Immune Senescence)

Although comorbidities substantially predispose older adults to infection, there is an underlying waning of immune responses that accompany old age even in the absence of comorbidity; this is called immune senescence. Immune senescence is not merely a global state of reduced immunity but a dysregulation of immune responses at multiple levels. A complete review of immune senescence is beyond the scope of this chapter, but both innate and adaptive responses are significantly dysregulated.

Innate immune responses are increased in some respects but decreased in others. Critical innate immune components that decline with age include physical barriers such as skin integrity, cough/gag reflex, mucociliary clearance, and gastric acid. Innate immune responses are also dysregulated at the cellular level, with impaired polymorphonuclear neutrophil function and dysregulation of inflammatory responses triggered by pathogen-associated molecular patterns via Toll-like receptors (Fig. 310.1). Despite impaired stimulus-triggered responses, there is often a chronic, low-level inflammation present in older adults. The cause(s) of this low-level inflammation is not well elucidated, but it likely plays a role in chronic disease development (e.g., vascular inflammation) and inhibitory mechanisms engaged to keep this low-level inflammation in check may be a cause, in part, of the slower innate response to infection seen in older adults.

In the adaptive immune system, there are decreases in naïve T-cell subsets, with an accumulation of memory T cells, substantially reduced diversity of the overall T-cell pool, and impaired responses to a specific antigen (Fig. 310.2).

Although there is little doubt that immune senescence exists, the clinical role of this phenomenon in the predisposition of older adults to clinical infection is poorly defined. Immune senescence markers have been extensively studied in vaccine responses measured most often by antibody titers and other surrogate markers, but only a few studies have been powered to assess clinical outcomes. It is quite clear that age itself is associated with reduced responses to vaccines as early as the third or fourth decade (human papillomavirus, hepatitis B), but the deficit grows throughout adulthood such that the efficacy of influenza and pneumococcal vaccines is questionable by the eighth and ninth decades. Specific vaccine formulations, very different from those used to boost early childhood responses, have been developed to try to overcome immune senescence; these include greater antigen concentration (e.g., high-dose influenza vaccine) or mixed-action adjuvants (e.g., zoster subunit vaccine) and appear to substantially mitigate immune senescence, not only enhancing postvaccine markers of immunity but reducing clinical disease risk.

Approach to the Patient with Malaria

Development of Malaria Immunity

Immunity to malaria is not an absolute, protective, sterilizing immunity, but rather a more suppressive type. Persons from malaria-endemic areas, repeatedly exposed to the parasite, develop a relative immunity that inhibits parasite multiplication, rendering the individual an asymptomatic carrier with very low densities of parasites in the blood, which do not cause any harm. The time to develop such immunity depends on the level of transmission and the exposure to malaria infection. In highly endemic (holoendemic) areas, children >5 years of age rarely suffer acute malaria, whereas, in areas with less endemicity, acute malaria is common also in older children. In areas of low endemicity or epidemic outbreaks, immunity may never develop. Expatriates who do not necessarily share the same degree of exposure as indigenous populations should be considered non-immune. Similarly, persons who have grown up in endemic areas but who have lived for long periods in non-endemic countries lose this type of immunity. When they return to their countries of origin, often to visit friends and relatives (VFR), they form a high-risk group for developing malaria.4 Chemoprophylaxis is often neglected.

Cerebral Toxoplasmosis

Immunity-Related GTPase (IRG) Family

The immunity-related GTPases (IRGs) are a family of proteins induced by IFNγ that are important in resistance against a wide variety of intravacuolar bacterial and parasitic pathogens, including T. gondii (Taylor et al., 2004, 2007; Zhao et al., 2009b). Of the hundreds of genes increased by IFNγ, the IRG genes are amongst the most abundant. These proteins, formerly called the p47 GTPases, were first described in the 1990s, and in the last decade, numerous studies have established the role of IRG proteins in resistance to Toxoplasma (Hunn et al., 2011; Zhao et al., 2009b). Most of the work has involved the following seven IRG members: Irgm1 (LRG-47), Irgm2 (GTPI), Irgm3 (IGTP), Irga6 (IIGPI), Irgb6 (TGTP), Regd (IRG-47) and Irgb10. Most of these IRG proteins are associated with inhibition of T. gondii in vitro, and of the four IRG genes that have been knocked out (Irgm1, Irgm3, Irga6, and Regd), all have been found to significantly increase susceptibility to infection of T. gondii, thus establishing the role of IRG proteins in resistance to T. gondii in mice.

The IRG proteins are 46–47 kDa GTPases, containing a Ras-like GTP-binding domain (termed G1). The IRG protein family consists of two subfamilies, based upon the nucleotide-binding domain within the G1 GTP-binding domain with one subfamily having a GM's amino acid motif and the other subfamily having a GKS motif. The three IRG members of the GMS subfamily include Irgm1, Irgm2, and Irgm3 while IRG members, Irga6, Irgb6, Regd, and Irg10 belong to the GKS subfamily. The GMS IRG proteins are regulators of GKS proteins binding to the GKS IRG proteins and maintaining them in the inactivated state via a GDP-dependent interaction (Hunn et al., 2008). The IRG genes are present throughout the vertebrate phyla, being present in cephalochordates, amphibians, fish, reptiles, and mammals. In mice, the IRG family is diverse, encoding approximately 23 genes, 21 of which encode proteins (Bekpen et al., 2005). The IRG family, however, seems to have been repeatedly lost during evolution with no IRG genes present in any of the available bird genomes and the number of IRG genes in humans dramatically reduced with only two IRG genes, IRGC and IRGM, present (Bekpen et al., 2009, 2010).

In IFNγ stimulated host cells infected with Toxoplasma multiple IRG proteins localize to the Toxoplasma parasitophorous vacuole membrane within minutes of invasion, with the parasitophorous vacuolar membrane subsequently becoming vesiculated and finally disrupted, resulting in the release of the parasite into the cytosol and degradation of the parasite (Martens et al., 2005; Ling et al., 2006; Melzer et al., 2008). In macrophages infected with Toxoplasma, destruction of the T. gondii is accompanied by the inclusion of the parasite in autophagosomes and subsequent autophagosomal delivery to the lysosomes (Ling et al., 2006; Butcher et al., 2005). IRG-mediated vacuolar disruption also occurs in IFNγ-stimulated fibroblasts and astrocytes but the autophagy pathway was not found to be involved (Melzer et al., 2008; Zhao et al., 2009b; Martens et al., 2005). However, mice deficient in the autophagic regulator, atg5, are deficient in their ability to control T. gondii replication indicating the autophagic pathway is involved in some way (Konen-Waisman and Howard, 2007). Atg5 is necessary for the delivery of IRG proteins to the PV, although this appears to operate by a mechanism independent of the normal autophagy pathway (Zhao et al., 2008). Finally, in IFNγ-stimulated fibroblasts IRG-mediated PV disruption results in host cell necrosis, following the release of the parasite into the host cytoplasm, indicating destruction of the host cell may be part of the IRG mechanism in some cell types (Zhao et al., 2009b).

The IRG mechanism involves a coordinated loading of IRG GTPases on the Toxoplasma vacuole with at least six IRG proteins (Irgm2, Irgm3, Irga6, Irgb6, Regd, and Irg10) localizing to the Toxoplasma vacuole (Khaminets et al., 2010). The coating of the IRG proteins to the PV occurs within one hour of invasion and is hierarchical with Irgb6 and Irgb10 loading first. Upon infection with T. gondii, GKS proteins lose their interaction with GMS proteins and accumulate at the PV membrane (PVM) in the active GTP bound state leading to vesiculation and rupture of the PV (Hunn et al., 2008; Papic et al., 2008). Despite a large amount of information now understood about the molecular and biochemical aspects of IRG-mediated inhibition of T. gondii, the mechanisms involved in the vesiculation leading to PV disruption is still not understood. IRG proteins are related to the dynamin-type GTPases known to mediate vesicle formation and deformation of membranes and it has been suggested that IRG protein acts in an analogous fashion mediating vesiculation of the PVM, although this has not been demonstrated (Hunn et al., 2011).

The type I strains is resistant to IRG-mediated IFNγ inhibition (Steinfeldt et al., 2010; Howard et al., 2011). This deficiency in IFNγ mediated control is associated with a failure of accumulation of IRG proteins on the PVM (Zhao et al., 2009a). This is due largely to the polymorphic rhoptry kinase, ROP18, which in type I strains phosphorylates the GKS IRG proteins Irga6, Irgb6, and Irgb10, causing dissociation of IRG from the vacuole and inhibition of PV disruption (Zhao et al., 2009a; Steinfeldt et al., 2010; Fentress et al., 2010). Another rhoptry protein, ROP5, has been found to directly interact with IRG proteins, reducing IRG coating and inactivating IRG proteins (Fleckenstein et al., 2012; Niedelman et al., 2012). ROP5 can interact with IRGs in the absence of ROP18. However, rhoptry proteins, ROP5 and ROP18 while mediating inhibition in IFNγ-activated murine cells, do not affect survival in IFNγ-activated human cells (Niedelman et al., 2012). These results suggest that while ROP5 and ROP18 may have evolved to block the IRGs they may not have effects on parasite survival in species that do not have the IRG system, such as humans. Why the IRGs are such a large family of proteins in the murine genome and so reduced in humans, or if functional counterpart(s) exists in humans, is not yet clear.