AIDS, Secondary Immunodeficiency and Immunosuppression

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Chapter 17 AIDS, Secondary Immunodeficiency and Immunosuppression

Summary

• Nutrient deficiencies often lead to impaired immune responses. Malnutrition increases the risk of infant mortality from infection through reduction in cell-mediated immunity, including reduced numbers and function of CD4+ helper cells and a reduction in levels of secretory IgA. Trace elements, iron, selenium, copper, and zinc are also important in immunity. Lack of these elements can lead to diminished neutrophil killing of bacteria and fungi, susceptibility to viral infections, and diminished antibody responses. Vitamins A, B6, C, E, and folic acid are likewise important in overall resistance to infection. Proper diet and nutrition, therefore, reduce morbidity and mortality caused by infection.

• Some drugs selectively alter immune function. Immunomodulatory drugs can severely depress immune functions. These drugs are often necessary to treat solid organ transplant patients and those with an autoimmune disease. Although necessary in such settings, these drugs are often broad acting, thereby increasing patients’ susceptibility to a broad array of opportunistic infections caused by viruses, bacteria and fungi.

• HIV is a primary cause of immunodeficiency. Human immunodeficiency virus (HIV) is a retrovirus that predominantly targets CD4+ T cells. Acute infection depletes CD4 T cell subsets and transiently suppresses circulating CD4 T cell numbers before the immune system establishes partial control of the virus and the chronic phase of infection begins. Though patients can remain in the chronic phase for an average of 10 years, without anti-retroviral drug treatment, CD4 T cell levels gradually fall, resulting in loss of cell-mediated immunity and susceptibility to life-threatening opportunistic infections. This final stage, AIDS (acquired immunodeficiency syndrome), is marked by low CD4 T cell counts, high HIV plasma levels, reactivation of other latent infections, and often, virus-associated malignancies such as Kaposi’s sarcoma and non-Hodgkin’s lymphoma.

• Combination therapy for AIDS with inhibitors of HIV reverse transcriptase, protease, and entry are reasonably successful, but associated with long-term toxicities in almost 50% of persons. An effective vaccine remains an elusive goal, in part due to the rapid mutation rate of the virus during reverse transcription.

Overview

Secondary immunodeficiencies are acquired and disrupt the development or function of an otherwise normal immune system. Unlike primary immunodeficiencies that are due to genetic abnormalities and often have a very defined presentation in the clinic, secondary defects are both more common and more heterogeneous. Therapeutic approaches for secondary immune deficiencies usually involve treating the primary extrinsic stressor, combined with increased vigilance for infection, as well as pharmacologic intervention or prophylaxis to address active or potential infections. Major causes of secondary immunodeficiency include:

• malnutrition;

• viral infection (e.g. HIV);

• iatrogenic immune suppression (e.g. post-organ transplant);

• cancer metastases or leukemias, especially those involving bone marrow;

• cancer treatments such as chemotherapy or irradiation;

• surgery or trauma;

• chronic disease, debility, or stress;

• advanced age.

Nutrient deficiencies

Globally, malnutrition is the most common cause of immunodeficiency. The connection between nutrition and immunity has a long historic record with periods of famine preceding periods of pestilence. As a primary diagnosis, malnutrition is a treatable problem that can range from severe protein-energy malnutrition (PEM) to marginal deficiencies in a single micronutrient. Immune responses are significantly impaired when calories, macronutrients or any key micronutrients are in limiting supply, leaving the undernourished at increased risk for infection.

Infection and malnutrition can exacerbate each other

Malnutrition and infection act synergistically to depress immunity and increase morbidity and mortality. Presence of infection often exacerbates the malnourished state by:

• increasing metabolic demands;

• decreasing appetite, thereby lowering intake of nutrients; and

• with gastrointestinal infection, decreasing nutrient absorption.

Once this cycle begins, it is self-propagating as infection compromises immunity, which then leads to more infection and debility (Fig. 17.1). At a population level, this may lead to decreased productivity, further decreasing economic and food resources and, again, driving the malnutrition and immune deficiency loop.

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Fig. 17.1 Malnutrition and infection exacerbate each other in a vicious circle

Malnutrition and infection exacerbate each other in a vicious circle.

Risk factors for malnutrition include poverty, food scarcity, illiteracy, and chronic debilitation. The impacts of malnutrition are seen globally. The World Health Organization (WHO) estimates worldwide, 50% of childhood deaths are due to malnutrition, many in developing nations. However, malnutrition is not just a problem of the poorest countries. In the USA, it is estimated that less than 50% of the elderly are adequately nourished, and even within populations that consume adequate calories, poor dietary nutrient intake can cause marginal nutrient deficiencies with a significant detrimental impact on morbidity and mortality.

Addressing the individual impact of any single micronutrient on immune function is difficult as the malnourished often present with multiple deficiencies. In order to understand the role of nutrients in immune function, many studies have assessed the correlates of both PEM and individual micronutrients on infection rates and immune responses. For example, in one study of surgical and trauma patients, those who presented with lower levels of serum albumin were found to have an increased risk for infectious complications. In addition to such population studies, both in vitro studies on human immune cells and in vivo animal studies have helped elucidate the direct effects of malnutrition on immunity. In some cases, the mechanisms underlying the effects of single nutrient-deficient diets have been determined. We present an overview of these findings below.

Protein–energy malnutrition and lymphocyte dysfunction

Though not all of the underlying mechanisms are clear, multiple studies have correlated PEM with defects in all aspects of the immune system defense, but especially cell-mediated immunity. Lymphoid atrophy is a prominent morphological feature of malnutrition. The thymus, in particular, is a sensitive barometer in young children and the profound reduction in weight and size of the organ effectively results in nutritional thymectomy. Both increased apoptosis of immature CD4+CD8+ thymocytes and a decrease in proliferation contribute to thymic involution. Atrophy is evident in the thymus-dependent periarteriolar areas of the spleen and in the paracortical section of the lymph nodes. Decreases in the thymic hormones, thymulin and thymopoeitin, accompany this loss in cellularity. Histologically:

• the lobular architecture is ill defined;

• there is a loss of corticomedullary demarcation;

• there are fewer lymphoid cells; and

• Hassall’s corpuscles are enlarged and degenerate – some may be calcified.

Thus, with PEM there is a significant decrease in circulating T cell numbers, with CD4 T cells disproportionately affected giving a low CD4+/CD8+ ratio. Functional studies in mice fed protein-deficit diets have shown that both low T cell precursor number and decreased proliferative response of the remaining lymphocytes upon antigen encounter contribute to an inability to clear viral infection.

Mechanistically, PEM may contribute to lymphocyte functional deficits due to limits in the availability of the amino acid glutamine, required for both nucleotide synthesis and cytokine production, as well as by the increase in oxidative stress. PEM additionally causes imbalances in the neuroendocrine signals affecting lymphocyte survival. Glucocorticoids, released during stress, are increased with PEM, while leptin levels are decreased. Leptin, a hormone released from adipose tissues, has pleiotropic effects, but in mice it can protect thymocytes from glucocorticoid-induced apoptosis. It is not surprising then, that PEM significantly diminishes cell-mediated immunity.

B cell functional deficits are less pronounced in PEM. Although serum antibody levels are usually normal, clinical studies have found a reduction in the secretory IgA antibody response to common vaccine antigens, which may contribute to a higher incidence of mucosal infections.

Nutrition also affects innate mechanisms of immunity

Poor nutrition also causes deficits in innate immune defenses, for example,

• a larger number of bacteria bind to epithelial cells of malnourished subjects;

• wound healing is impaired;

• the production of certain inflammatory cytokines, such as IL-2 and TNFα, is decreased;

• opsonization is decreased, largely because of a reduction in levels of various complement components – C3, C5, and factor B.

Q. How would a decrease in complement components affect innate immunity?

A. Decreased opsonization and killing of extracellular microorganisms increases susceptibility to bacterial infections (Chapter 4).

Deficiencies in trace elements impact immunity

Zinc is one of several trace elements essential for optimal immune system function. WHO estimates that about one third of the world’s population is affected by some level of zinc deficiency. At particular risk are populations with plant-based diets, as fiber and phytate in plant foods inhibit zinc absorption. Similar to protein deficiencies, zinc deprivation can cause severe progressive involution of the thymus, with significant, rapid reduction in thymic weight, primarily due to cortical region loss. Zinc is a structural element both in the peptide hormone, thymulin, as well as in many transcription factors. Thus, reduction in the activity of thymulin contributes to thymic and lymphoid atrophy, and decreased activity of factors such as NFκB prevents adequate IL-2 and IFNγ production impairing cell-mediated immune responses. NK cell lytic activity is also diminished with zinc deficiency.image

Zinc deficiency during pregnancy has also been shown to have an inter-generational effect on the levels of IgM and IgM producing B cells in the pups, and more surprisingly even in the 2nd generation (Fig. 17.w1).

image

Fig. 17.w1 Intergeneration effects of zinc deficiency on immunity

An experimental group of animals was fed a zinc-deficient diet (5 ppm Zn) during the later two-thirds of pregnancy and a control group was fed a zinc-adequate diet (100 ppm Zn) during the same period. The former regimen reduced serum Zn to 60×70% of control values. F1, F2, and F3 generations were fed sufficient zinc throughout. Both the PFC response and serum concentration of IgM were assessed at 6 weeks. Results showed that both were low in at least three generations of offspring.

Iron deficiency results in a reduced ability of neutrophils to phagocytose or kill bacteria and fungi as well as decreased lymphocyte response to mitogens and antigens, and impaired NK cell activity. Iron is a double-edged sword as iron-dependent enzymes have crucial roles in lymphocyte and phagocyte function while iron bioavailability favors growth of many microorganisms.

Q. In what ways can neutrophils and macrophages restrict iron availability for microorganisms?

A. Soluble proteins such as lactoferrin produced by neutrophils reduce the availability of free iron in the phagolysosome. Macrophages have ion pumps (e.g. nRAMP) in their phagosomal membrane that remove iron from the phagosome (see Chapter 15).

Selenium, incorporated as the amino acid selenocysteine, is an important component of the antioxidants catalase and glutathione peroxidase. In vitro, selenium deficiency leads to decreased T cell responses, decreased NK cell function, and altered cytokine production. There is some correlation between low selenium levels and disease progression in HIV-infected patients, and with increased viral titers in patients receiving attenuated polio virus; however, the impact of selenium supplementation on anti-viral immunity remains unclear.

Vitamin deficiencies and immune function

Singular deficiencies in vitamins B1, B6, and B12 are rare; however, as with all nutrients, severe deficits impact immune responses. In vivo studies examining the effects of B vitamin deficiencies, both in humans and animal models, typically show impairment of thymic and lymphoid cellularity, decreased proliferative responses, and decreased antibody production. Vitamin C and vitamin E have known antioxidant functions. Serum Vitamin C levels quickly diminish with stress or infection. Treatment of DCs in vitro with vitamin C can mediate p38 and NFκB activation augmenting IL-12 secretion. Vitamin E treatment of macrophages, via its antioxidant role, can decrease production of PGE2.

Q. How might an increase on IL-12 secretion or a decrease in PGE2 affect immune responses?

A. As PGE2 normally suppresses IL-12 production, the overall increase in IL-12 would favor TH1 type responses.

Other work has likewise documented the immunoregulatory effects of Vitamin A on immune function. Vitamin A deficiency, which is endemic in developing nations, impairs epithelial and mucosal barriers, leading to hyperplasia, loss of mucus-producing cells, and susceptibility to gastrointestinal infection. Additionally, there is a reduction in the number and function of certain lymphocyte subsets, especially those of the gut-associated lymphoid tissue, contributing to overall defects in IgA levels.

Q. NFATc1, a member of the NFAT transcription factor family, is required for development of the B-1 B cell subset. Recent experiments using mice have shown that vitamin A deficiency severely reduces NFAT-c1 expression resulting in loss of the B-1 population. Why might this contribute to defects in mucosal immunity?

A. B1 cells are self-renewing cells that make significant contribution to the mucosal IgA response and are important in maintaining homeostasis with commensal gut bacteria.

Until the advent of antibiotics, cod liver oil and sunlight, both sources of vitamin D, were used as primary treatments for TB. Vitamin D deficiency can lead to increased infection rates and recent studies have begun to elucidate some of the molecular mechanisms behind the anti-infective role of vitamin D. Many cell types express the vitamin D receptor (VDR), and while vitamin D metabolites may modulate adaptive immune responses, they can also enhance innate immunity. Importantly, particularly for TB, signaling via the VDR may enhance both cathelicidin and defensin expression, thus boosting macrophage anti-microbial activity (Chapter 7).

Multiple studies in vitamin A-deficient animals have shown that supplementation of vitamin A or its metabolites enhances immune responses to vaccination and production of antibodies to both T-dependent and polysaccharide antigens. However, the health benefit of incorporating vitamin A supplements into vaccination programs for diseases such as measles, polio, diphtheria, pertussis and tetanus has been equivocal. There is some evidence that failure in some studies to actually correct the vitamin A deficiency may, in part, account for poor results. Finally, it is important to note that malnutrition due to insufficient intake or absorption is rarely one dimensional. Thus, interpretation of such studies where individual micronutrients are supplemented must take into account that other nutrient deficiencies may remain.

Obesity is associated with altered immune responses

Although the mechanisms remain unclear, obesity increases susceptibility to both nosocomial and post-surgical infections and increases risk of serious complications from common infections. Obese subjects and animals show alteration in various immune responses, including:

• cytotoxicity;

• NK activity; and

• the ability of phagocytes to kill ingested bacteria and fungi.

Altered levels of some micronutrients, lipids, and hormones may explain these immunological changes.

Immunodeficiency secondary to drug therapies

Several classes of drugs suppress immune function, either intentionally for therapeutic effect, or as an unwanted side effect.. For example, patients receiving organ transplants usually receive a variety of immunosuppressants to prevent rejection of the donor tissue and to treat graft-versus-host disease (GvHD, discussed in Chapter 21). Likewise, patients presenting with severe inflammatory, allergic, or autoimmune reactions often require therapeutic immunosuppression (Chapter 20

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