Immunology (Lippincott Illustrated Reviews Series) 2nd Edition

Chapter 15: Immune Deficiency

I. OVERVIEW

Sometimes it seems as if the immune system is so complicated that it cannot possibly work. Failure seems almost assured, and indeed, small deficits in the generation of T- and B-cell receptors are common (see Chapter 8). Because redundancy is built in, failure in one component of the immune system may sometimes be covered by another component with a similar or overlapping function. In other cases, failures in immune function become overt and may have a severe clinical impact.

Overt failures of the immune system leave the affected individual with a reduced ability to resist infection. Immune deficiencies or immunodeficiencies caused by defects in various components of the immune system are infrequent, although not insignificant, and occur in two different ways. Primary immune deficiencies are those caused by intrinsic or congenital defects. These deficiencies usually are genetic in nature, but they may sometimes appear as the result of randomly occurring errors in development. Over 100 primary immune deficiency diseases have been identified in humans, and for many of these diseases, the specific defective genes have been identified.

Primary immunodeficiency diseases were once considered rare, but many are actually more common than was previously thought. Selective IgA deficiency has a frequency of about 2 individuals per thousand, compared with numerous others that occur with frequencies of 1 to 10 per hundred thousand. However, because there are so many different primary immunodeficiency diseases, they become a significant health problem when considered collectively. Most primary immune deficiencies become apparent at about 6 months of age, when the maternally derived antibodies that entered the fetal circulation in utero begin to disappear and the infant becomes dependent on his or her own immune system.

Secondary immune deficiencies are caused by environmental causes such as infection, therapeutic treatments, cancer, and malnutrition. These deficiencies may occur at any time of life, depending on when the exposure to the causative factor(s) occurs. As with primary immune deficiencies, affected individuals are more susceptible to infection.

Immune deficiencies are characterized by several features. Some features occur in most forms of immunodeficiency, and some occur with a more limited set of deficiencies. Still others are associated only with specific diseases. These disease-specific features are often useful in diagnosis of a particular individual’s disease.

Characteristics seen in many immune deficiency diseases include the following:

• Recurrent or chronic infections

• Inability to clear infectious agents after standard antibiotic therapy

• Unusual infectious agents

Characteristics seen in a limited set of immune deficiency diseases include the following:

• Failure of infants to gain weight normally, known as failure to thrive (severe combined immune deficiency disease [SCID], interferon-γ receptor deficiency, bare lymphocyte syndrome)

• Hepatosplenomegaly (common variable immune deficiency [CVID], interferon-γ receptor deficiency, Chediak–Higashi syndrome)

• Skin rashes (SCID, Wiskott–Aldrich syndrome [WAS], X-linked agammaglobulinemia)

• Diarrhea (associated with gastrointestinal infection) (CVID, WAS, X-linked agammaglobulinemia, bare lymphocyte syndrome, SCID, chronic granulomatous disease [CGD])

• Recurrent abscesses (CGD, leukocyte adhesion molecule defects)

Nonimmunologic characteristics that occur in specific immune deficiency diseases include the following:

• Platelet deficiency (thrombocytopenia) (Wiskott–Aldrich syndrome)

• Loss of balance (ataxia) and widened blood capillaries (telangiectasia) (immunodeficiency with ataxia telangiectasia)

• Partial or complete albinism (Chediak–Higashi syndrome)

II. PRIMARY (CONGENITAL) IMMUNE DEFICIENCIES

Defects causing primary immune deficiencies may occur in different cell lineages: the combined lymphoid cell lineage, T- or B-cell lineages separately, lineages producing phagocytic cells and natural killer (NK) cells, and even cells producing complement components. Additionally, defects in cells of one lineage may affect the development of other lineages that are intrinsically normal. For example, abnormalities in T cells may prevent the activation of B cells that are otherwise normal. And the interactions between cells from different lineages may result in a single defect inhibiting multiple types of immune responses.

Autosomal gene defects (whether recessive or dominant) affect both sexes equally. However, defective X-linked genes (usually recessive) affect males far more frequently than females. Unlike females, males cannot compensate for a defective X-linked gene with a normal counterpart of that gene on the other X chromosome.

A. Defects in stem cells

The pluripotent stem cells that ultimately generate the granulocytic, erythrocytic, monocytic, thrombocytic, and lymphocytic lineages of the hematopoietic system are initially found in the aorta-gonad-mesonephros of the developing embryo. These cells undergo two migrations. During embryonic and fetal development, they migrate to the fetal liver. Later, before birth, they migrate again, this time to the bone marrow, where they remain for life. Some of the pluripotent stem cells differentiate into slightly differentiated stem cells that give rise to each of the five hematopoietic lineages (Fig. 15.1). Lymphoid stem cells generate both B cells (B-1 and B-2) and T cells (αβ and γδ). Recall from Chapter 7 that the B-2 cell lineage remains within the bone marrow for development, the B-1 lineage relocates to and self-replicates in the peritoneal/pleural tissues, and the T-cell lineage migrates to the thymus.

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Figure 15.1

Hematopoietic stem cells and lineages. Pluripotent stem cells in the bone marrow give rise to all five hematopoietic cell lineages: lymphocytes, thrombocytes, monocytes, granulocytes, and erythrocytes. Note that both the lymphocytic and monocytic lineages produce dendritic cells.

Defects in lymphoid stem cells giving rise to both the T- and B-cell lineages result in defective function of both cell types (Fig. 15.2). Individual defects may result in abnormal T- and B-cell numbers or functions or both. Cell-mediated responses (e.g., cell-mediated lysis and delayed type hypersensitivity) are usually reduced, as is immunoglobulin production. The relative impacts of individual defects, however, are not always equal in T and B cells, nor do they always have equally severe consequences among affected individuals.

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Figure 15.2

Effects of lymphoid cell lineage deficiencies. Defects in the lineage producing both T and B lymphocytes impair the development and/or functionality of both types of lymphocytes.

Severe combined immunodeficiency (SCID) is the classic example of defects in the combined lymphocyte lineage. SCID is not a single disease; it is a group of diseases caused by different defects in individual genes that have similar functional consequences (Table 15.1). SCID-related defects may occur in the genes that encode enzymes (RAG-1, RAG-2) responsible for the rearrangements of DNA that produce the variable regions of immunoglobulins and T-cell receptors. Other examples include defects in cytokine receptors and in molecules involved in cell-to-cell interaction for the activation of lymphocytes. Defective production of purine nucleoside phosphorylase provides an example of a genetic defect that affects both T and B cells but with differing intensity. The accumulated toxic metabolites resulting from this defect impair the functions of T cells far more severely than those of B cells.

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CLINICAL APPLICATION

X-linked SCID

Luca D., a 4-month-old male, presents with severe diarrhea and failure to thrive. Over the past 2 months, he has had two episodes of ear infections requiring antibiotic therapy. Examination reveals a poorly nourished child with minimal tonsillar tissue and the presence of oral thrush. Blood tests reveal lymphocyte counts significantly below normal with an absence of T cells (CD3+) and NK cells (CD16+, CD56+) and significantly reduced numbers of B cells (CD19+). A further workup by an immunology consultant indicates a diagnosis of X-linked SCID. The hematology/immunology transplant team is notified, and the patient receives a bone marrow transplant.

B. Defects in T cells

Primary immune deficiencies intrinsic to T cells result in abnormal T-cell numbers and/or functions. However, because T-cell “help” is critical to the activation of naive and memory B cells, many T-cell defects also cause abnormalities in B-cell numbers and immunoglobulin production (Fig. 15.3). Several representative diseases resulting from T-cell defects are given in Table 15.2. Some are common to both CD4+ and CD8+ T cells; some affect only one T-cell type or the other. Because the delayed-type hypersensitivity response is largely responsible for clearance of fungi, frequent or recurrent fungal infections are suggestive of defects in T-cell function.

A second category of T-cell defects comprises those in which the responsible mutation(s) are not limited to T cells but may occur in cells that are critical to the development or activation of T cells. Some T-cell defects arise from mutations in other cells that influence the development or activation of T cells. For example, TAP-2 deficiency (also known as bare lymphocyte syndrome I) is caused by defects in the transporter associated with the antigen presentation (TAP; either TAP1 or TAP2) system. These defects ultimately impair the loading of peptide fragments into nascent MHC class I molecules in all nucleated cells and reduce the number of MHC class I molecules that successfully reach the cell surface. This reduced MHC I expression decreases the number of functional CD8+ T cells and can also affect the functions of NK cells monitoring MHC class I expression on body cells (although the NK cells appear not to attack uninfected host cells). Likewise, defects inhibiting expression of MHC class II molecules reduce the number of functional CD4+ T cells. An additional example is DiGeorge syndrome (see Table 15.2) in which defects in thymic development arising from abnormal embryonic changes in the third and fourth pharyngeal pouches may inhibit or prevent development and thymic education of T cells. The severity of effects of DiGeorge syndrome is variable. In addition to abnormal development of the pharyngeal pouches, the syndrome may include malformations of the aorta, the face and jaw, and the parathyroid glands. Most individuals with DiGeorge syndrome carry small deletions in chromosome 22, although the relevant gene or genes and their functions are still unidentified. These associated features allow early detection and treatment of DiGeorge syndrome at birth.

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Figure 15.3

Effects of T-lymphocyte deficiencies. Defective T cells not only reduce cell-mediated immune responsiveness, but also often reduce B-cell functions because of the regulatory role for T cells in B-cell activation.

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C. Defects in B cells

Several inherited genetic defects are intrinsic to B cells (Fig. 15.4). These B-cell defects are responsible for the majority (more than 80%) of human immunodeficiency diseases (Table 15.3). Immunoglobulin levels are typically affected, but not necessarily B-cell numbers. Some B-cell deficiencies are characterized by abnormal production of all immunoglobulin isotypes, whereas others affect only one or a few. T-cell numbers and functions are typically normal. The following examples illustrate the range of effects seen.

X-linked (Brutonagammaglobulinemia, a recessive X-linked disorder, is one of the best known B-cell immunodeficiencies, resulting from a defect in the gene (BTK) that encodes Bruton tyrosine kinase, an enzyme that is crucial to the early development of B cells. Consequently, in this disorder, B cells are few in number, and all immunoglobulin isotypes are diminished. Defects in several autosomal genes also lead to aberrant B-cell development and similar agammaglobulinemias.

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Figure 15.4

Effects of B-lymphocyte deficiencies. Defective B cells affect humoral responses by altering B-cell numbers and/or functions, including immunoglobulin production. T cell functions are usually unaffected.

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CLINICAL APPLICATION

X-linked (Bruton) agammaglobulinemia

X-linked (Bruton) agammaglobulinemia was named after an American pediatrician, Dr. Ogden Carr Bruton. In 1952, Dr. Bruton described the clinical case of an 8-year-boy who had recurrent bacterial infections, including many episodes of pneumococcal sepsis. Dr. Bruton vaccinated the boy, but the patient did not produce any antibodies to Pneumococcus. In fact, the boy did not produce antibodies to any antigen and had undetectable levels of serum immunoglobulins. Dr. Bruton treated this patient with monthly injections of exogenous gamma globulin. The boy did not have any occurrences of sepsis over the 14 months during which he received injections. Because this condition was observed only in male patients, it was determined to be X-linked.

CLINICAL APPLICATION

Common variable immunodeficiency

Martha D., a 40-year-old woman, presents with recurrent sinusitis requiring antibiotic treatment. She has had two hospitalizations within the past 2 or 3 years for bacterial pneumonia. She also reports symptoms of chronic diarrhea, abdominal pain, weight loss, and fatigue. Laboratory tests reveal evidence of malabsorption because of infection with Giardia lamblia. Serum immunoglobulin assessments reveal a significantly decreased level of IgG and a mildly decreased level of IgA, consistent with common variable immunoglobulin deficiency. She is treated with passive immunoglobulin therapy, and her IgG level increases to within normal range. She continues to receive immunoglobulin therapy and remains free of significant infection or diarrhea for several years thereafter.

Selective IgA deficiency is the single most common immune deficiency disease, with a frequency estimated at one to two per thousand individuals. Multiple gene defects produce it, and there is evidence that some forms of the disease may involve defective isotype switch signaling from T cells. Individuals with selective IgA deficiency have normal levels of other isotypes and often display additional immunologic disorders (e.g., allergy or autoimmunity).

B-cell activation is dependent in part on interaction with helper CD4+ T cells. Some of this interaction involves the binding of CD40 on T cells to CD154 (CD40-ligand) on B cells. Immune deficiency with hyper-IgM results from a defect in the gene encoding the CD40 ligand. As a result, the isotype switch does not occur normally, and individuals with this defect produce high levels of IgM but are deficient in B cells that produce IgG, IgA, or IgE.

D. Defects in phagocytes and natural killer cells

Immune deficiency may also result from defects in nonlymphocytic cells such as phagocytes, neutrophils, and NK cells (Fig. 15.5, Table 15.4). Defects in phagocytic cells are significant because of their key roles in both innate and adaptive immune responses. The defects affect two major functions of these cells: their ability to kill microbes and their interactions with other cell types.

Several defects can interfere with the phagocyte’s microbe-killing function. Defects in the genes associated with chronic granulomatous disease (CGD) result in defective enzymes and other microcidal molecules (e.g., toxic oxygen metabolites) involved in destruction and degradation of ingested microbes. In contrast, individuals with Chediak–Higashi syndrome have normal levels of these enzymes and microcidal molecules, but a defect in organelle membranes inhibits the normal fusion of lysosomes (carrying the enzymes and microcidal molecules) with phagosomes (containing the ingested microbes). Consequently, the phagocytes fail to destroy ingested microbes. Defects in receptors (e.g., pattern recognition receptors, IFN-γ receptors) used by phagocytic cells to respond to external activation signals can also leave the affected individuals susceptible to bacterial infections.

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Figure 15.5

Effects of phagocytic cell and natural killer cell deficiencies. Defects in phagocytic cells reduce the ability to ingest and degrade microbes and to engage in antigen presentation to T cells. Defective NK cells have reduced ability to kill virally infected cells and participate in development of Th1 immune responses.

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A second group of defects (e.g., leukocyte adhesion defect 1 [LAD-1] and LAD-2 deficiencies) inhibit accessory cell function, including the ability of these cells to migrate and interact with other types of cells. For example, some leukocytes must interact with vascular endothelium to move from the vasculature into the tissues. Leukocytes of affected individuals may be unable to migrate to the organs in which lymphocyte activation occurs and to sites of infections, where they are needed to destroy and clear the infectious agents.

E. Defects in the complement system

Deficiencies in the complement system can affect both innate and adaptive immune responses (Fig. 15.6, Table 15.5). Numerous gene defects involving complement components and regulatory molecules increase susceptibility to infection and sometimes to the risk of autoimmune disorders as well. In general, defects in the alternative pathway and mannan-binding lectin (MBL) pathways lead to increased susceptibility to infection. Defects in the classical pathway (except for C3) are not associated with significantly increased susceptibility to infection except for those caused by encapsulated bacteria. In these infections, antibodies, complement, and neutrophils are all required simultaneously to opsonize and kill these bacteria. C3 deficiency results in severe problems with recurrent infection and with immune complex-mediated disease because of the central position of C3 in all three of the complement activation pathways.

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Figure 15.6

Effects of complement system deficiencies. Defective complement components can impair opsonization, lytic killing of microbes (via the membrane attack complex), and the ability to induce inflammation. Defects in regulatory components can lead to uncontrolled episodes of inflammation.

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The MBL and alternative pathways are able to generate sufficient complement-mediated protection against infection, even in the absence of the classical pathway. Deficiencies in the components of the alternative pathway (e.g., C3, B, D) are associated with increased susceptibility to infection. Deficiencies in C1, C2, and C4 can lead to inefficient clearance of immune complexes, increasing the risk of type III hypersensitivity diseases and injury to kidneys, joints, skin, and blood vessels (see Chapter 14).

Deficiencies in regulatory complement components can also cause disease. The most common is hereditary angioedema (or hereditary angioneurotic edema), in which reduced levels of C1 inhibitor reduce the ability to control activation of the classical pathway. As a result, uncontrolled inflammatory episodes occur that can become serious when the vascular system, respiratory tract, and GI tract are affected. Deficiencies in decay accelerating factor (DAF) or CD59 allow accumulation of complement complexes, including the membrane attack complex, on host cell membranes with ensuing cell injury.

III. SECONDARY (ACQUIRED) IMMUNE DEFICIENCIES

Some immunodeficiency diseases arise not from genetic or developmental causes but from environmental exposures. These diseases are called secondary immune deficiencies. They may occur at any time of life, depending on when exposure occurs (Table 15.6). Among the environmental factors that can induce immune deficiencies are therapeutic treatments, infections, malignancy, and general health.

A. Physiologic sequelae

Many factors that affect the overall health of the body can impair immune function. Stress, for example, has been associated not only with reduced general health, but also with impaired immune function. Among the most investigated of these environmental factors is nutrition. Malnutrition has been shown to diminish the immune system’s ability to protect against infection. In some cases, reduced levels of specific dietary components have been shown to play a role in immunodeficiency. The amino acid glutamine, for example, is critical for normal levels of energy metabolism, and shortages of certain minerals and vitamins have been implicated in reduced immune function. Various reports indicate that reduced levels of iron, zinc, selenium, and vitamins A, B6, C, and E are also associated with impaired immune function.

B. Therapeutic treatment

A normal individual’s immune system may become suppressed, either intentionally or as a side effect of medical treatment (see Chapter 18). Transplant recipients usually undergo treatment to inhibit their immune responsiveness, at least for a period of time (see Table 15.6), to heighten the chances of survival for the grafted tissue. During this treatment (and sometimes afterward), transplant recipients have a heightened susceptibility to opportunistic infection and must be monitored and treated to avoid the onset of overwhelming infection.

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Similarly, individuals with autoimmune diseases (see Chapters 16 and 18) may be treated with agents that diminish the immune responses that are causing their problems, but again, such treatment often leaves them more susceptible to opportunistic infection. Treatments aimed at other medical problems, such as cancer therapy, also injure the immune system as they are directed at cells undergoing rapid division.

C. Infection

As was discussed in Chapter 13, many infectious organisms circumvent or evade immune responses generated against them. In many cases, these evasive tactics leave the host more susceptible to other infectious agents as well. For example, some bacteria secrete enzymes that destroy local immunoglobulins and complement components. Some bacteria and viruses protect themselves after ingestion by phagocytes by inhibition of several key phagocyte activities: fusion of phagosomes with lysosomes, synthesis and release of microcidal molecules, and presentation of peptides by MHC class I (pMHC I) molecules. Yet other microbes (e.g., Plasmodium) evade the immune system by living within cells such as erythrocytes that express neither MHC class I nor II molecules on their surfaces. As a result, T cells cannot detect whether such cells are infected or not. Finally, some infectious organisms influence the entry of naive T cells into either the Th1 or Th2 pathways, whichever is least effective for clearance of those particular microbes.

HIV (human immunodeficiency virus) destroys CD4+ T cells, leading to acquired immune deficiency syndrome (AIDS). HIV can also infect and kill monocytes and even CD8+ T cells as the infection progresses. Because CD4+ T cells are so central to the development of numerous immune responses, their progressive loss produces a gradual decline in humoral and cellular responses and an increasing susceptibility to opportunistic infection that eventually becomes fatal.

In 2009, an estimated 33.3 million people were living with HIV/AIDS worldwide, most in sub-Saharan Africa. According to the Joint United Nations Programme on HIV/AIDS 2009 report, some 60 million people worldwide have been infected with HIV, and 25 million have died of HIV-related causes since the epidemic began. Since the early 1990s, however, the number of new cases of AIDS- and HIV-related deaths has decreased significantly owing to effective antiviral therapies. These decreases have been most evident in the United States and Europe thus far (Fig. 15.7). The availability of antiviral therapy in other parts of the world has begun to improve, and there is hope that it will eventually provide similar benefit.

CLINICAL APPLICATION

HIV infection and AIDS

AIDS (acquired immune deficiency syndrome) is caused by HIV (human immunodeficiency virus). HIV is a retrovirus that damages the cells of the body’s immune system. People with HIV may develop opportunistic infections and various forms of cancer. The Centers for Disease Control and Prevention CDC) defines AIDS as laboratory confirmation of HIV infection and CD4+ T cell count of 200 cell/mL; or CD4+ T cell percentage of <14; or documentation of an AIDS-defining condition (with laboratory confirmation of HIV infection). Among the AIDS-defining conditions are candidiasis of the esophagus, cryptococcosis (extrapulmonary), histoplasmosis (disseminated or extrapulmonary), Pneumocystis jirovecii pneumonia, and Mycobacterium tuberculosis infection of any site.

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Figure 15.7

Impact of HIV/AIDS in the USA. Although the number of persons with HIV/AIDS has continued to increase in the USA, the availability of antiviral treatment is associated with deceases in the number of new cases and the numbers of deaths.

The CD4 molecule expressed on subsets of human T cells, dendritic cells, and macrophages is the major means by which HIV binds and enters cells. However, it also uses two chemokine receptor molecules as coreceptors for the two types of cells that are preferentially infected: CCR5 on macrophages and dendritic cells and CXCR4 on lymphocytes (Fig. 15.8). In the absence of these coreceptors, HIV is unable to successfully enter the cells. A small percentage of individuals of Caucasian descent fail to express CCR5 and are protected from infection by HIV. Infection of CD4+ CCR5+ dendritic cells appears to be the primary route of initial infections; infection of CD4+ CXCR4+ 
T cells occurs later in the disease process.

D. Cancer

Cancerous lymphocytes reduce the immune system’s ability to respond to different antigens by overgrowing the rest of the lymphocyte population. As a result, the immune repertoire becomes limited as it is dominated by fewer and fewer clones of lymphocytes. Lymphocytes and other monocytes that become malignant (lymphomas and leukemias) can begin to crowd out the ability of normal hematopoietic cells to maintain proper levels. They often also begin to display aberrant surface molecules and alter their normal production of cytokines, antibodies, and other molecules. As a result, they can induce immune deficiencies by abnormal interactions with other parts of the immune system. In one interesting example, individuals with Waldenström macroglobulinemia secrete such excessive amounts of immunoglobulins that the viscosity of the blood is increased.

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Figure 15.8

Coreceptors for cell infection by HIV. In addition to the CD4 molecule, HIV requires either CCR5 or CXCR4 to successfully enter and infect a cell.

IV. TREATMENT OF IMMUNE DEFICIENCIES

Several methods have been used to attempt restoration of deficient immune functions or to alleviate their consequences. Some provide only temporary benefits and must be regularly repeated, whereas other approaches carry the potential for permanent cure.

A. Passive supplementation

The passive administration or supplementation of deficient components can often be beneficial, although the benefits are usually temporary. Injection of intravenous immunoglobulin, for example, provides exogenous antibodies that boost insufficient intrinsic immunoglobulin levels. Cytokines or even enzymes (e.g., in patients with adenosine deaminase deficiency) can also be administered passively. Passive therapies must be repeated at regular intervals, however, because the injected cells or molecules have finite half-lives. In some cases, even cells can be passively transferred for temporary effect.

B. Bone marrow transplantation

For long-term or permanent deficiencies, passive administration may be effective but requires constant repetition. In some cases, there may also be a risk of serum sickness. Replacement by engineered stem cells may provide a means to a permanent cure. A bone marrow transplant from a suitable donor currently offers the most effective means of replacing a damaged immune system. The requisite stem cells for lymphocytes, phagocytes, neutrophils, eosinophils, mast cells, and basophils are all present in the transferred bone marrow. Except for conditions in which immune deficiencies arise from sources outside of the hematopoietic system (e.g., DiGeorge syndrome), replacement of an immunodeficient patient’s bone marrow with marrow from a normal donor should provide a permanent source of normal immune components.

Because bone marrow transplantation involves placement of immunocompetent tissues into immunoincompetent recipients, it is possible for the transplanted tissue to react against the recipient. Mature, immunocompetent T cells present in the transplanted marrow might view the recipient as nonself and attack the host cells (graft-versus-host disease) unless they are carefully removed prior to the transfer (see Chapter 17). Bone marrow transplantation has become increasingly effective as the techniques involved have been refined.

C. Genetic engineering

Advances in genetic engineering have permitted replacement of defective cells with “repaired” cells. An individual’s defective cells are removed, engineered in vitro to replace defective genes with functional ones, and inserted into back into the patient. However, numerous procedural difficulties have limited the use of this technique. First, unless the repaired cells are stem cells, the procedure constitutes passive therapy and will have to be repeated as the injected cells die. Second, once injected, the engineered cells must be able to migrate properly to the sites where they can grow and develop normally. Third, the “repaired” genes must be appropriately regulated and expressed, and the engineered cells must respond appropriately to signals affecting the expression and secretion of the new gene products. Finally, one must consider the risk that the engineering might lead to a malignant transformation or some other aberrant behavior in the engineered cell population.

Several successful attempts to treat immune deficiencies have been performed at the National Institutes of Health involving patients suffering from ADA deficiency, and in some cases, the engineering involved stem cells. Although many of these patients have received considerable benefit, full functional replacement of sufficient numbers of stem cells has not yet been achieved, and the patients continue to receive periodic passive administration of engineered cells. It is hoped that continued research will improve the efficacy of these procedures.

Chapter Summary

Primary immune deficiencies are caused by intrinsic genetic or congenital defects. More than 100 primary immunodeficiency diseases are known in humans, and the specific defective genes are known for many of them. Defects causing primary immune deficiencies occur in various cell lineages, affecting different sets of cells/molecules.

Secondary immune deficiencies are caused by environmental factors such as infection, therapeutic treatments, cancer, and malnutrition. They may occur at any time of life, depending on when the exposure to the causative factor(s) occurs.

Severe combined immunodeficiency (SCID) is caused by defects in the combined lymphocyte lineage that impair T- and B-cell functions. SCID is actually a group of diseases caused by different individual genetic defects (autosomal and X-linked) that have similar functional consequences.

TAP deficiency is a condition in which defects in the transporter associated with the antigen presentation (TAP) system impair the loading of peptide fragments into nascent MHC class I molecules in all nucleated cells. As a result, the number of MHC class I molecules that successfully reach the cell surface is reduced.

DiGeorge syndrome results from defects in thymic development that prevents normal development and thymic education of T cells. DiGeorge syndrome varies in the severity of effects and may be accompanied by abnormalities caused by abnormal development of embryologically related tissues: the aorta, the face and jaw, and the parathyroid glands.

X-linked (Bruton) agammaglobulinemia is a recessive X-linked disorder resulting from a defective gene (BTK) that encodes Bruton tyrosine kinase, an enzyme crucial to the early development of B cells. B cells are reduced in number or absent.

Selective IgA deficiency is the single most common immune deficiency disease, with a frequency estimated at one to two per thousand individuals.

Immune deficiency with hyper-IgM results from a defect in the gene encoding the CD40 ligand (CD154). As a result, the isotype switch does not occur normally, and individuals with this defect produce high levels of IgM but are deficient in B cells that produce IgG, IgA, or IgE.

• Defects in several different genes causing chronic granulomatous disease (CGD) encode defective enzymes and other microcidal molecules (e.g., toxic oxygen metabolites) involved in destruction and degradation of ingested microbes.

Chediak–Higashi syndrome results from an inability to fuse lysosomes (carrying enzymes and microcidal molecules) with phagosomes (containing ingested microbes).

• Some immunodeficiencies (e.g., leukocyte adhesion defect 1 [LAD-1] and LAD-2 deficiencies) arise from defects in molecules needed for leukocytes to migrate and interact with each other or other cell types.

Hereditary angioedema, caused by reduced levels of C1 inhibitor, reduces the ability to control activation of the classical pathway.

HIV (human immunodeficiency virus) destroys CD4+ T cells, leading to acquired immune deficiency syndrome (AIDS).

• Injection of intravenous immunoglobulin provides exogenous antibodies that boost insufficient intrinsic immunoglobulin levels.

• For long-term or permanent deficiencies, replacement of an immunodeficient patient’s bone marrow with marrow from a normal donor may provide a permanent restoration of immune function. The requisite stem cells for lymphocytes, phagocytes, neutrophils, eosinophils, mast cells, and basophils are all present in the donated bone marrow.

Study Questions

15.1. A 2-month-old male infant presents with persistent diarrhea, signs and symptoms of Pneumocystis carinii pneumonia, and an oral fungal infection with Candida albicans. His weight is in the 10th percentile. Test results for HIV are negative by polymerase chain reaction. The most likely cause of these findings is

A. grossly reduced levels of B cells.

B. an X-linked inheritance of HLA genes.

C. defective isotype switching.

D. defective T-cell function.

E. selective IgA deficiency.

The correct answer is D. The fungal infection is highly suggestive of a T-cell defect. Choices A, C, and E do not of themselves imply a deficiency in T-cell function. HLA genes are autosomal, not X-linked.

15.2. A 5-year-old girl has a small deletion in chromosome 22. She has impaired thymus development with a significant deficiency in the number of functional T cells. The most likely etiology for these findings is

A. adenosine deaminase (ADA) deficiency.

B. Chediak–Higashi syndrome.

C. DiGeorge syndrome.

D. hereditary angioedema.

E. severe combined immunodeficiency (SCID).

The correct answer is C. Impaired thymic development leading to T-cell dysfunction and small deletions in chromosome 22 are characteristic of DiGeorge syndrome. Thymic development is normal in all of the other choices.

15.3. A 3-year-old boy with an X-linked defect in the Bruton tyrosine kinase (BTK) gene is impaired in which of the following mechanisms?

A. Antibody-mediated bacterial clearance

B. Formation of the membrane attack complex

C. Delayed (-type) hypersensitivity (DTH) 
responses

D. IFN-γ secretion by CD4+ T cells

E. T-cell precursor migration to the thymus

The correct answer is A. Bruton agammaglobulinemia results in a near or total absence of B cells and immunoglobulins; hence antibody-mediated responses to microbes are severely impaired. Even in the absence of antibodies and the classical pathway of complement activation, the membrane attack complex can be generated through the MBL and alternative pathways. Antibodies are not involved in the other choices.

15.4. A 6-month-old male infant has diarrhea, extensive fungal infections, and skin rashes and has failed to gain weight. He is deficient in both T- and B-cell function. The thymus is of normal size. The most likely prospect for permanent restoration of normal immunity for this patient would be

A. an antibiotic “cocktail” given at regular intervals.

B. bone marrow transplantation.

C. exogenous immunoglobulins administered 
periodically.

D. isolation to an antiseptic environment.

E. thymic hormones given throughout his life.

The correct answer is B. The signs suggest a defect in the lymphocytic lineage. This could potentially be permanently alleviated by replacement of defective stem cells through bone marrow transplantation. Isolation is beneficial but is a severe imposition on the quality of life and constitutes protection rather than restoration of function. The remaining choices require constant repetitive application but not permanent restoration of function.

15.5. A female neonate has a malformed jaw, cardiac abnormalities, and hypocalcemia, in addition to diminished cell-mediated and B-cell responses. Which of the following immune deficiencies should be included in the differential diagnosis of this patient?

A. Adenosine deaminase (ADA) deficiency

B. DiGeorge syndrome

C. Hereditary angioedema

D. Severe combine immunodeficiency disease (SCID)

E. Wiskott–Aldrich syndrome

The correct answer is B. The defects in jaw and cardiac structure and the defective calcium metabolism (because of abnormal parathyroid development) point to aberrant development of structures derived from the third and fourth pharyngeal pouches. None of the other diseases given are associated with these accompanying features. This individual is likely to also include the thymus, and this patient is likely to have an underdeveloped thymus, which is a hallmark of DiGeorge syndrome.

15.6. A 21-year-old woman has a history since childhood of recurrent episodes of swelling of the submucosal and subcutaneous tissue of the gastrointestinal and respiratory tracts. Her C1 inhibitor level is less than 5% of the reference value. These findings support a diagnosis of

A. DiGeorge syndrome.

B. hereditary angioedema.

C. nutrition-based immune deficiency.

D. paroxysmal nocturnal hemoglobinuria.

E. Wiskott–Aldrich syndrome.

The correct answer is B. Hereditary angioedema is caused by deficient levels of C1 inhibitor. DiGeorge syndrome is caused by aberrant development of the thymus. Nutrition-based immunodeficiencies are not characteristically identified by severely reduced levels of specific cell types or related molecules. Paroxysmal nocturnal hemoglobinuria is caused by a deficiency of CD59, and Wiskott–Aldrich syndrome is caused by a deficiency of the Wiskott–Aldrich syndrome protein.

15.7. A 3-month-old male infant has recurrent infections and is found to have an impaired ability to kill microbes by the nitroblue tetrazolium test (which evaluates effectiveness of degradative enzymes). Which of the following conditions is most likely responsible for the findings in this patient?

A. Chediak–Higashi syndrome

B. Chronic granulomatous disease

C. Hereditary angioedema

D. HIV/AIDS

E. Waldenström macroglobulinemia

The correct answer is B. Chronic granulomatous disease is caused by defects in various degradative enzymes or other molecules involved in the oxidative burst. Chediak–Higashi syndrome is caused by an inability to fuse lysosomes with phagosomes. HIV/AIDS results from progressive destruction of CD4+ T cells. Although HIV can infect macrophages and dendritic cells, they remain capable of normal phagolysosome function. Hereditary angioedema results from a deficiency in C1 inhibitor, and Waldenström macroglobulinemia is caused by excessive production of IgM.

15.8. A 24-year-old male presents with fever, cough, and night sweats. Examination reveals an elevated temperature, increased respiratory rate, oral thrush (fungal infection), and decreased breath sounds in the right midlung field. Laboratory testing reveals a CD4 count of 60/mL (reference range: 400/mL). On the basis of these findings, the most likely underlying process is

A. autoimmune disease with pneumonia.

B. bacterial pneumonia.

C. HIV/AIDS with possible mycobacterium tuberculosis.

D. hypersensitivity pneumonitis.

E. Mycobacterium tuberculosis infection only.

The correct answer is C. The key feature is the extreme deficiency of CD4+ T cells that is characteristic of HIV/AIDS. None of the other choices would be associated with this finding. Respiratory difficulties caused by Mycobacterium tuberculosis infection are frequently seen in HIV/AIDS patients.