Alterations in Immunity

Type I hypersensitivity reactions require sensitization against a particular environmental antigen (allergen) that results in a primary immune response. The response occurs when the immune system first encounters an antigen (primary exposure) and forms antigen-specific memory B cells and T cells (immunologic memory). Disease symptoms appear after secondary exposure to the offending antigen when memory cells are rapidly activated against the same antigen (see Chapter 8). These reactions occur within minutes to a few hours after exposure to antigen and are termed immediate hypersensitivity reactions.

When allergens enter the body of a genetically predisposed individual, they are detected by dendritic cells and B cells, then undergo antigen processing and presentation (Fig. 9.1A). T helper (Th) cells are activated to produce large amounts of the Th2 cytokines, especially interleukin (IL)-4, IL-5, and IL-13. High levels of IL-4 and IL-13 cause B cells to proliferate and become plasma cells that produce antigen-specific IgE. IL-5 recruits and activates eosinophils, which contain granules full of enzymes that are especially damaging to the respiratory system (see Chapter 36). Other interleukins such as IL-9 and IL-33 also play a role in exacerbating type I hypersensitivity reactions.^2,3

IgE has a relatively short life span in blood because it rapidly binds to Fc receptors (antibody receptors) on mast cells. The Fc receptors on mast cells specifically bind IgE that has not previously interacted with antigen. After a large amount of IgE has bound to the mast cells, an individual is considered sensitized. When there is a secondary or reexposure of a sensitized individual to the allergen, the IgE antibodies signal the mast cells to degranulate and release mediators.

Mast cells release a variety of cytokines (Fig. 9.1B). Histamine is the most potent preformed mediator of IgE-mediated hypersensitivity. Histamine acts immediately (within 15 to 30 minutes) and affects several key target cells. The tissues most commonly affected by type I responses contain large numbers of mast cells and are sensitive to the effects of histamine released from them. These tissues are found in the gastrointestinal tract, skin, and respiratory tract. Acting through histamine 1 (H1) receptors, histamine contracts bronchial smooth muscles (bronchial constriction), increases vascular permeability (edema), and causes vasodilation (increased blood flow) (see Chapter 7).

Mast cells also synthesize secondary mediators, such as leukotrienes, prostaglandins, and platelet activating factor, which act more slowly (within hours) and have effects similar to that of histamine (see Fig. 9.1B). These newly formed mediators also attract other immune cells (e.g., eosinophils, neutrophils, basophils, monocytes), activate kinins, and initiate the complement cascade with release of the anaphylatoxins C3a, C4a, and C5a (see Chapter 7). These mediators are responsible for a late phase reaction that sets in 2 to 24 hours later even without additional exposure to antigen and may last for several days. The overall effect of these cytokines is inflammation of affected tissues leading to vasodilation, mucous secretion, bronchoconstriction, and tissue injury.

Arthus reaction is vasculitis caused by repeated local exposure to an antigen that reacts with preformed antibody and forms immune complexes in the walls of the local blood vessels. Symptoms of Arthus reaction begin within 1 hour of exposure and peak 6 to 12 hours later. The lesions are characterized by a typical inflammatory reaction, with increased vascular permeability, an accumulation of neutrophils, edema, hemorrhage, clotting, and tissue damage. For example, gluten-sensitive enteropathy (celiac disease) follows ingestion of antigen, usually gluten from wheat products (see Chapter 42). Allergic alveolitis (farmer lung disease, pigeon breeder disease) is Arthus-like acute hemorrhagic inflammation of the air sacs (alveoli) of the lungs, resulting from inhalation of fungal antigens, usually particles from moldy hay or pigeon feces (see Chapter 35).

Allergic type IV reactions are elicited by some environmental antigens that are haptens and become immunogenic after binding to larger (carrier) proteins in the individual. In allergic contact dermatitis, the carrier protein is in the skin. The best-known example is the reaction to poison ivy (Fig. 9.5). The antigen is a plant catechol, urushiol, which reacts with normal skin proteins and evokes a cell-mediated immune response. Skin reactions to industrial chemicals, cosmetics, detergents, clothing, food, metals, and topical medicines (e.g., penicillin) are elicited by the same mechanism. Contact dermatitis consists of lesions only at the site of contact with the allergen, as in metal allergy to jewelry.

Top panel, A, is an illustrated flowchart showing the development of type 4 hypersensitivity to poison ivy. Catechol molecules from poison ivy combines with the skin proteins on humans. • 7 to 10 days: T cells to T memory cells, no dermatitis. Primary contact. • 1 to 2 days: T memory cells to many active cells, dermatitis. Secondary contact. Bottom panel, B, is a closeup of a hand affected by dermatitis. The skin appears dry and cracked on the fingers and on the surface below the index finger.

Genes and environment interact in complex ways in individuals with type I hypersensitivity.4 Certain individuals are genetically predisposed to develop type I IgE-mediated hypersensitivity and are called atopic. In families in which one parent has an allergy, allergies develop in approximately 40% of the offspring. If both parents have allergies, the incidence in the offspring may be as high as 80%. Atopic individuals tend to produce higher quantities of IgE and to have more Fc receptors for IgE on their mast cells. The airways and the skin of atopic individuals are also more responsive to a wide variety of both specific and nonspecific stimuli than are the airways and skin of individuals who are not atopic. Multiple genes have been associated with the atopic state, including polymorphisms in a large variety of cytokines that regulate IgE synthesis (e.g., IL-4, IL-13) and cellular receptors.

The environment has a significant impact on allergic disease. Diet, medications, and comorbidities impact the microbiome and the health of the adaptive immune system (see Emerging Science Box: The Microbiome and Food Allergy).⁵ In genetically predisposed individuals, exposure to large quantities of allergens and irritants in the environment can trigger symptoms. The role of infection in allergic disease is complex and may be protective or may render organ systems such as the respiratory tract more vulnerable to allergic symptoms.

The clinical manifestations of allergy are attributable mostly to the biologic effects of histamine. Tissues most commonly affected contain large numbers of mast cells and are sensitive to the effects of histamine released from them. These tissues are found in the gastrointestinal tract, skin, and upper and lower respiratory tracts (Fig. 9.6). The particular symptoms frequently reflect the main portal of entry for the allergen. For instance, pollens and other airborne allergens usually cause respiratory symptoms.

An illustration shows the anterior view of a human, with the internal organs highlighted. The following conditions are highlighted on the illustration: • Head: itching. • Eye: conjunctivitis. • Nose: rhinitis. • Cheek: angioedema (an accompanying closeup shows a person’s eye swollen shut). • Neck: laryngeal edema. • Shoulders: urticaria (an accompanying closeup shows a person’s shoulders and back, covered in welts). • Lungs: bronchospasm (asthma). • Heart: dysrhythmias. • Upper arm (attached with a blood pressure gauge): hypotension. • Intestines: gastrointestinal cramps and malabsorption. • Hands and genitalia: angioedema.

Effects of allergens on the mucosa of the eyes, nose, and respiratory tract include conjunctivitis (inflammation of the membranes covering the front of the eye and the lining the eyelids), rhinitis (inflammation of the mucous membranes of the nose), and asthma (constriction and swelling of the bronchi). Symptoms of all these conditions are caused by vasodilation, hypersecretion of mucus, edema, and swelling of the mucosa. Because the mucous membranes lining the respiratory tract (accessory sinuses, nasopharynx, and upper and lower respiratory tracts) are continuous, they are all adversely affected. The degree to which each is affected determines the symptoms of the disease. One of the most common type I reactions is asthma. It is presented in detail in Chapter 35. The central problem in asthma is obstruction of the large and small airways (bronchi) of the lower respiratory tract by bronchospasm (constriction of smooth muscle in airway walls), edema, and thick secretions. This leads to ventilatory insufficiency, wheezing, and difficult or labored breathing.

Urticaria, or hives, is a dermal (skin) manifestation of type I allergic reactions (see Fig. 9.6). The underlying mechanism is the localized release of histamine and increased vascular permeability, resulting in limited areas of edema. Urticaria is characterized by white fluid-filled blisters (wheals) surrounded by areas of redness (flares). The wheal and flare reaction is usually accompanied by itching. Not all urticarial symptoms are caused by allergic (immunologic) reactions. Some, termed nonimmunologic urticaria, result from exposure to cold temperatures, emotional stress, medications, systemic diseases, hyperthyroidism, or malignancies (e.g., lymphomas).

Gastrointestinal allergies are caused primarily by allergens that enter through the mouth—usually foods or medicines. When food is the allergen, the active immunogen may be a product of food breakdown by digestive enzymes. Acute symptoms usually occur rapidly (frequently within minutes) and include vomiting, diarrhea, or abdominal pain. Prolonged or recurrent reactions may result in malabsorption or protein-losing enteropathy. Systemic symptoms may range from urticaria to life-threatening anaphylactic reactions. The most common food allergies are tree nuts, peanuts, milk, shellfish, and fish. The prevalence of food allergies is estimated at 3% to 10% of adults and 8% of children worldwide.⁶ The most rapid and severe allergic reaction is anaphylaxis. Anaphylaxis occurs within minutes of reexposure to the antigen and can be either systemic (generalized) or cutaneous (localized). Symptoms of systemic anaphylaxis include pruritus, erythema, vomiting, abdominal cramps, diarrhea, and breathing difficulties, and the most severe reactions may include contraction of bronchial smooth muscle, edema of the throat, and decreased blood pressure that can lead to shock and death (see Chapter 48). Examples of systemic anaphylaxis are allergic reactions to antibiotics, bee stings, or peanuts.

Some type I allergic responses can be controlled by blocking histamine receptors with antihistamines. The effects of allergy on the respiratory system may require bronchodilators or medications that block leukotrienes (see Chapter 35). The most effective medications for allergic disease are the corticosteroids, which can be given by local administration (e.g., inhalers or topical ointments) or systemically to decrease tissue inflammation. For individuals with severe allergy, monoclonal antibodies that block IgE may be required (omalizumab). Other monoclonal antibodies that block IL-4 (dupilamab) and IL-5 (mepolizumab) are now available. In anaphylaxis, systemic administration of sympathomimetic medications such as epinephrine may be required to support the respiratory and cardiovascular systems (see Chapter 48).

Heparin-induced thrombocytopenia (HIT) is a common complication associated with the use of the anticoagulant drug heparin (see Chapter 29). Heparin serves as a hapten and forms molecular complexes with the tissue-specific platelet antigen called platelet factor 4 (PF4). These hapten/antigen complexes are then attacked by autoantibodies causing type II hypersensitivity. When these autoantibodies bind to the surface of platelets, they cause two problems. The first is that they destroy platelets, leading to thrombocytopenia and bleeding. The second is that the destroyed platelets release particles that activate thrombin, forming clots that can block blood vessels (thrombosis).¹³

Approximately 2% of individuals treated with heparin will develop clinically significant HIT.¹⁴ To diagnose HIT, laboratory tests are done to document thrombocytopenia and/or thrombosis and to look for the presence of the autoantibodies. Management requires stopping heparin therapy and, if anticoagulation is still needed, substituting with a nonheparin anticoagulant.¹³

Systemic lupus erythematosus (SLE) is one of the most common, complex, and serious of the autoimmune disorders. It can affect any organ in the body. SLE is characterized by the production of a large variety of antibodies (autoantibodies) against self-antigens, including nucleic acids, erythrocytes, coagulation proteins, phospholipids, lymphocytes, platelets, and many other self-components. The most characteristic autoantibodies are against nucleic acids (e.g., single-stranded deoxyribonucleic acid [ssDNA], double-stranded DNA [dsDNS]), histones, ribonucleoproteins, and other nuclear materials. The blood normally contains many of these products of cellular turnover and breakdown. In SLE, autoantibodies react with the circulating antigen and form circulating immune complexes. The deposition of circulating DNA/anti-DNA complexes in the kidneys can cause severe kidney inflammation (Fig. 9.7). Similar reactions can occur in other systems, such as the brain, heart, spleen, lung, gastrointestinal tract, peritoneum, and skin. Thus many of the symptoms of SLE result from a type III hypersensitivity reaction and affect many systems. Other symptoms are related to type II hypersensitivity reactions and include destruction of red blood cells (anemia), lymphocytes (lymphopenia), and platelets (thrombocytopenia).

SLE, like most autoimmune diseases, occurs more often in women (approximately a 9:1 predominance of females), especially in the 20- to 40-year-old age group.15 Blacks are affected more often compared with Whites (approximately an eightfold increased risk). Several genes have been identified that are associated with an increased risk for SLE, including changes in MHC molecular structure.^16,17 Environmental triggers (e.g., ultraviolet radiation exposure, smoking, medications, viruses such as Epstein-Barr virus [EBV], low vitamin D levels, environmental pollutants) and hormonal changes interplay with genetic predisposition in disease development and activity.¹⁸ As in many autoimmune conditions, microbiome dysbiosis is thought to negatively impact adaptive immune responses in SLE.¹⁹

As with other autoimmune diseases, clinical manifestations of SLE may wax and wane; the individual may go through periods of remission and be relatively disease free until the onset of a flare (exacerbated disease activity). Clinical manifestations of SLE depend on organ systems involvement, including skin (rashes and photosensitivity), eyes (keratoconjunctivitis, scleritis, uveitis retinopathy), mucus membranes (ulcers), joints (arthralgias), linings of the viscera (serositis, pleuritis), kidney (proteinuria), blood (anemia), gut (abdominal pain, vasculitis, hepatobiliary disease), and the neurologic system (seizures or psychosis).²⁰ Lupus nephritis is common and carries a high risk for end-stage renal failure. Cardiovascular disease is common.²¹ Fever also may be present. Classification of SLE is based on the type and severity of organ system damage along with measurement of antibodies and complement levels.²²

Laboratory diagnosis is usually based on a positive antinuclear antibody (ANA) screening test. This is a very sensitive test, but a substantial number of false-positive results occur in healthy individuals and those with other diseases. Detection of ANAs is usually followed by one or more specific tests (e.g., antibodies against Smith antigen [Sm], and dsDNA).²⁰ Further diagnostic testing may be indicated such as urinalysis and serum C reactive protein and complement levels.

There is no cure for SLE or most other autoimmune diseases. Fatalities resulting from SLE are usually related to infection, organ failure, or cardiovascular disease. The goals of treatment are to control symptoms and prevent further damage by suppressing the autoimmune response. Ultraviolet light may initiate flares, and protection from sun exposure is helpful. Nonsteroidal antiinflammatory drugs (NSAIDs), such as ibuprofen, reduce inflammation and relieve pain. Hydroxychloroquine is the preferred treatment for individuals with stable disease. Corticosteroids are often prescribed for flares and more serious active disease. Immunosuppressive drugs, (e.g., methotrexate, cyclophosphamide, azathioprine, tacrolimus, or mycophenolate mofetil) are used to treat severe symptoms. Immunotherapies focused on B-cell depletion (e.g., belimumab, rituximab) are used in selected individuals.²³ Many new biologic agents, such as anifrolumab (anti–type I interferon receptor antibody) and ustekinumab (antibody against IL-12/23 [p40]), are in clinical trials.²⁴

The ABO blood group consists of two major carbohydrate antigens, labeled A and B (Fig. 9.8), that are expressed on virtually all cells. These are codominant so that both A and B can be simultaneously expressed, resulting in an individual having any one of four different blood types. The erythrocytes of blood type A express the type A carbohydrate antigen, those with blood type B express the B antigen, those with blood type AB express both A and B antigens on the same cell, and those of blood type O express neither the A nor the B antigen. A person with type A blood also has circulating antibodies to the B carbohydrate antigen. If this person receives blood from a type AB or B individual, a severe transfusion reaction occurs, and the transfused erythrocytes are destroyed by agglutination or complement-mediated lysis. Similarly, a type B individual (whose blood contains anti-A antibodies) cannot receive blood from a type A or AB donor. Type O individuals, who have neither antigen but have both anti-A and anti-B antibodies, cannot accept blood from any of the other three types. These naturally occurring antibodies, called isohemagglutinins, are IgM antibodies developed early in life because of the presence of similar antigens expressed on naturally occurring bacteria in the intestinal tract.

A series of illustrations shows A B O blood types. The erythrocyte for O blood type comprises H antigen, and the antibody in serum comprises anti-A and anti-B. The erythrocyte for A blood type comprises A antigen and H antigen, and the antibody in serum comprises anti-B. The erythrocyte for B blood type comprises B antigen and H antigen, and the antibody in serum comprises anti-A. The erythrocyte for A B blood type comprises A antigen, B antigen, and H antigen, and the there are no antibody in serum.

Harmful transfusion reactions can be prevented by complete and careful ABO matching between donor and recipient. Because individuals with type O blood lack both types of antigens, they are considered universal donors—that is, anyone can accept their red blood cells. Similarly, type AB individuals are considered universal recipients because they lack both anti-A and anti-B antibodies and can be transfused with any ABO blood type.

Hemolytic disease of the fetus and newborn (HDFN) (also known as erythroblastosis fetalis) is a condition in which maternal blood antigens do not match those of the fetus. This disorder usually results from incompatibility between maternal and fetal red blood cell (erythrocyte) Rho(D) antigens. The Rh blood group is a group of antigens expressed on red blood cells. This is the most diverse group of red blood cell antigens, consisting of at least 45 separate antigens, although only one is considered of major importance: the D antigen. Individuals who express the D antigen on their red blood cells are Rh positive, whereas individuals who do not express the D antigen are Rh negative. Approximately 85% of North Americans are Rh positive. Rh-negative individuals make IgG antibody to the D antigen (anti-D) if exposed to Rh-positive erythrocytes. In an Rh-negative mother whose fetus is Rh-positive, antibodies from the mother cross the placenta and attack fetal erythrocytes. The attack induces severe anemia in the fetus (erythroblastosis fetalis) or in the newborn (erythroblastosis neonatorum). With each successive pregnancy with an Rh-positive fetus, the mother’s immune system makes anti-D antibodies faster and in greater amounts. Diagnosis involves measurement of maternal antibodies and fetal testing. Prenatal and postnatal management may include intrauterine transfusions, exchange transfusions, intravenous immunoglobulin (IVIG), or plasmapheresis.25 The occurrence of this particular form of the disease has decreased dramatically because of the use of prophylactic anti-D immunoglobulin (i.e., RhoGAM). Administration of anti-D antibody within a few days of exposure to RhD-positive erythrocytes prevents sensitization against the D antigen (see Chapter 30).

Molecules of the major histocompatibility complex (MHC) were discussed in Chapter 8 as antigen-presenting molecules (see Figs. 8.6 and 8.7). MHC molecules also are a major target of transplant rejection. The human MHC molecules are also referred to as human leukocyte antigens (HLAs), especially in the context of transplantation. The different MHC genetic loci are identified as class I: HLA-A, HLA-B, and HLA-C, and class II: HLA-DR, HLA-DQ, and HLA-DP (Fig. 9.9). Humans have two copies of each MHC locus (one inherited from each parent) that are codominant so that molecules encoded by each parent's genes are expressed on the surface of every cell, except erythrocytes. The tremendous number of possible alleles that can be expressed throughout the population makes it highly unlikely that any two unrelated individuals will have the same HLA antigens. This diversity of HLA molecules becomes clinically relevant during organ transplantation. The recipient of a transplant will mount an immune response against the foreign HLA antigens on the donor tissue, resulting in rejection. To minimize the chance of tissue rejection, the donor and recipient are tissue-typed to identify differences in HLA antigens prior to transplantation. The more similar the two individuals are in their HLA tissue type, the more likely it is that transplantation will be successful. The chance of finding a reasonably close match among siblings is much higher than the general population, and, clearly, the most successful transplants would be between identical twins because they are nearly identical genetically.

An illustration of chromosome 6 is labeled with the centromere and the short arms. The following protein classes are labeled on the short arm, from the outside toward the centromere: class 1, class 3, and class 2. The classification of the human leukocyte antigens (H L A) are as follows: • Class 1 M H C locus. From the right to the left: A, C, B. • Class 3 M H C locus. • Class 2 M H C locus. From the right to the left: D R, D Q, and D P.

When donor tissue is transplanted into a recipient, the recipient’s T cells recognize alloantigens in two different ways: (1) direct recognition of foreign HLA antigens, and (2) indirect recognition of donor peptides that are presented on recipient antigen-presenting cells (see Algorithm 9.1). Both processes result in the widespread activation and proliferation of Th cells. Th cells differentiate into several subtypes that produce numerous cytokines, including IL-2 and interferon (IFN)-γ (Th1 cells), IL-4 (Th2 cells), and IL-17 (Th17 cells) (see Chapter 8). These cytokines activate T cytotoxic cells, macrophages, NK cells, and B cells such that there is an intense cell-mediated and humoral attack on the graft tissue.

Transplant rejection may be classified as hyperacute, acute, or chronic, depending on the amount of time that elapses between transplantation and rejection and the mechanisms by which rejection occurs. Hyperacute rejection is immediate and rare. Hyperacute rejection occurs because of the presence of preexisting antibodies (type II hypersensitivity) to HLA antigens on the vascular endothelial cells in the grafted tissue. These preexisting antigens are usually found in individuals who have received multiple blood transfusions or previous transplants. When the circulation is reestablished to the grafted area, the graft may immediately turn white (the so-called white graft) instead of a normal pink color. Hyperacute rejection can be avoided by testing the recipient for preexisting antibodies prior to transplantation.

Acute rejection occurs within days to months after transplantation. This type of rejection occurs when the recipient develops an immune response against unmatched HLA antigens after transplantation. Both humoral and cell-mediated immune responses play a role (Algorithm 9.2). Direct and indirect recognition of alloantigens result in release of Th1, Th2, and Th17 cytokines. Alloantibodies are formed to graft blood vessels (type II hypersensitivity) which then activate complement, resulting in necrosis of graft vessels (vasculitis). Tc cells and macrophages are activated, resulting in direct lysis of graft cells and disruption of tissue architecture; this leads to graft dysfunction and destruction (type IV hypersensitivity). NK cells and other components of innate immunity also play a role. The release of IL-2 is of particular importance in acute rejection; thus several antirejection medications target IL-2 synthesis or receptors (e.g., cyclosporin, tacrolimus, basiliximab). Other antirejection medications deplete T- and B-cell numbers, metabolism, and function (e.g., mycophenolate mofetil, rituximab, prednisone, azathioprine, belatacept), or block inflammatory cytokines such as IL-6 (e.g., tocilizumab). New methods for achieving graft tolerance include adoptive transfer of donor and recipient Treg cells and myeloid-derived suppressor cells.^26,27 Studies are exploring the potential for modifying the epigenetic profiles of immune cells and the use of messenger RNA (mRNA) in the prevention of graft rejection.²⁸ The choice of immunosuppressive medications is based on the type of organ being transplanted and the potential for recipient toxicity.

An illustration flowchart demonstrates acute graft rejection. There are five stages of rejection. 1. Donor antigens recognized by recipient T cells via direct or indirect allorecognition. Recipient A P C (indirect) and donor graft cell (direct) bind to the T helper cell through M H C class 2, donor antigen, T C R, and C D 4. 2. T h 0 cells produce I L-2, proliferate, and differentiate into T h subsets. 3. T h 1, T h2, and T h 17 cells subsets activated. 4. Hypersensitivity reactions and inflammation. 5. Destruction of graft tissue with scarring. The result of activation of the different cells are as follows: • T h 1 cell secretes I L-2, I F N-gamma. Type 4 hypersensitivity (T cytotoxic cells and macrophages) leads to necrosis. An accompanying photomicrograph shows dead cells. • T h 2 cell secretes I L-4. Type 2 hypersensitivity (B cells and alloantibodies) leads to vasculitis. An accompanying photomicrograph shows inflamed blood vessels. • T h 17 cell secretes I L-17. Innate immunity (N K cells, cytokines) leads to fibrosis. An accompanying photomicrograph shows a network of fibrous connective tissue.

Chronic rejection may occur after a period of months or years of normal function. It is characterized by slow, progressive organ failure. Chronic rejection occurs most often in recipients who were poorly matched to their donor, have comorbidities (e.g., diabetes, hypertension), received a graft that was in poor condition or was damaged during the transplantation procedure, or have required treatment for multiple acute rejection episodes.

Chronic rejection involves several mechanisms. A cell-mediated (type IV hypersensitivty) reaction against minor histocompatibility antigens on the grafted tissue contributes to persistent Tc-cell and phagocyte activation. Th17 cytokines trigger chronic inflammation. There also is binding of alloantibodies to donor graft MHC molecules, resulting in complement activation and tissue destruction (late antibody-mediated rejection).29 These processes are subacute and slowly progressive, leading to graft fibrosis (scarring), dysfunction, and tissue death. Once chronic rejection is well established, there are few effective treatments, and it may be necessary to replace the graft with a new transplanted organ.

Severe combined immunodeficiencies (SCIDs) are the most common combined deficiency without nonimmunologic abnormalities. Most often, it is inherited in an autosomal recessive pattern, or it may be X-linked.32 There are at least 20 different forms of SCID, depending on how the underlying genetic defect affects lymphocyte development and function. T-cell differentiation is defective, and, depending on the type of SCID, B cells and NK cells also are affected.³² Most individuals with SCIDs have few detectable lymphocytes or NK cells in the circulation and secondary lymphoid organs (spleen, lymph nodes). Immunoglobulin levels, especially IgM and IgA, are absent or greatly reduced. The most severe form of SCID is due to reticular dysgenesis in which a common stem cell fails to develop into mature immune cells. Most children with this form of SCID die in utero or soon after birth.

Several forms of SCID are caused by autosomal recessive enzymatic defects that result in the accumulation of toxic metabolites, and rapidly dividing cells, such as lymphocytes, are especially sensitive. For instance, deficiency of adenosine deaminase (ADA deficiency) results in the accumulation of toxic purines. Enzyme replacement therapy is available for this form of SCID.³³X-linked SCID results from a common defect in important IL receptors needed for lymphocyte maturation (e.g., IL-2, IL-4, IL-7, and others). Recent reports demonstrate the remarkable effectiveness of gene therapy in which a lentivirus is used as a vector to insert a normal copy of the IL-2 receptor (IL-2R) gene into a person’s own hematopoietic stem cells.³⁴

Even if nearly adequate numbers of B and T cells are produced, their cooperation may be defective. Bare lymphocyte syndrome is the form of SCID characterized by the inability of lymphocytes and macrophages to produce MHC class I or class II molecules. Without MHC molecules, antigen presentation and intercellular cooperation cannot occur effectively. Children with this deficiency develop serious, life-threatening infections and usually die before age 5 years.

A SCID newborn screening test is available and has been in use in the United States since 2008. After an abnormal screening, additional testing is needed to determine which type of SCID is present.³⁵ This approach has resulted in prompt treatment and higher survival rates and is now performed for all newborns in the United States. Hematopoietic stem cell transplantation is the standard treatment for infants with SCID; unfortunately, it is not universally effective and can be associated with serious complications such as graft-versus-host disease (GVHD). New gene therapies are emerging for several forms of SCID.³⁶

Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by the clinical triad of low platelet count (thrombocytopenia), eczema, and recurrent infections, is a condition in which IgM antibody production is greatly depressed. WAS results from a mutation of the WAS gene which causes defects in the WAS protein (WASP). WASP is required for normal differentiation of B cells and several other hematopoietic cell types. For example, defective WASP affects the actin cytoskeleton, which is important for platelet function. Immunodeficiencies include reduced antibody responses against antigens that primarily elicit an IgM response, such as polysaccharide antigens from bacterial cell walls (e.g., Pseudomonas aeruginosa, Streptococcus pneumoniae, Haemophilus influenzae). Defective WASP also impacts neutrophil migration and function. Clinical manifestations include bleeding, eczematous rash, and recurrent infections (e.g., otitis media, pneumonia, herpes simplex, CMV). Autoimmune conditions (e.g., hemolytic anemia) are also common. Management includes IVIG or subcutaneous immunoglobulin (SQIG), stem cell transplantation, and gene therapy.37

Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome or velocardiofacial syndrome) is another combined immunodeficiency with syndromic features. Chromosome 22q11.2 deletion is the most common microdeletion genetic syndrome in humans.³⁸ This mutation is associated with a wide spectrum of phenotypes even within families. The deletion of a particular gene, T-box transcription factor 1 (TBX1), is thought to be responsible for many of the syndrome's characteristic signs and symptoms. The TBX1 gene provides instructions for making a protein called T-box 1. The T-box 1 protein is necessary for the development of muscles and bones of the face and neck, aorta, and the thymus and parathyroid glands.³⁹ In most cases, hypoplasia of the thymus results in greatly decreased T-cell numbers and function. Immunocompromise with susceptibility to infection is complicated by a shift in Th-cell function to Th2 predominance resulting in allergies, as well as a reduction in Treg function resulting in autoimmune disorders. Cardiac and endocrine problems are also common. Defective development of the third and fourth pharyngeal pouches during embryonic development results in thymic defects and the absence of the parathyroid gland (causing inability to regulate calcium concentration). Low blood calcium levels cause the development of tetany or involuntary rigid muscular contraction. This syndrome frequently is associated with abnormal development of facial features that are controlled by the same embryonic pouches; these include low-set ears, fish-shaped mouth, and other altered features (Fig. 9.10). Loss of this gene may also contribute to behavioral problems such as schizophrenia and bipolar disorder. Dopaminergic neurons are also affected, leading to an increased risk for development of Parkinson disease later in life.⁴⁰ Management includes monitoring and intervention for hypoparathyroidism, heart defects, facial abnormalities, infections, and neurologic complications. No specific treatment for the underlying condition is currently available.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immune deficiency, affecting up to 1 in 10,000 individuals.41 There are two peak ages of onset, one before the age of 10 and another between 30 and 40 years of age. As the name implies, the presentation is very heterogeneous. It is characterized by hypogammaglobulinemia, but the particular class of antibody that is decreased varies. Although B-cell numbers are normal, most individuals have low amounts of IgG, which may or may not be accompanied by decreased levels of IgA and IgM. Multiple genetic defects in terminal differentiation of B lymphocytes may account for this condition, although the pathogenesis remains poorly understood.⁴² Failure to produce sufficient immunoglobulins results in recurrent infections in 90% of individuals with CVID. Pneumonia caused by S. pneumoniae or H. influenzae, and infections with adenovirus, CMV, and varicella zoster are common.⁴¹ Secondary complications include arthritis (infectious and noninfectious), gastrointestinal symptoms (malabsorption, chronic diarrhea), autoimmune disease (anemia, thrombocytopenia, endocrine diseases), and cancer (of the lymphoid system, skin, and gastrointestinal tract).⁴³ Interstitial lung disease is a significant cause of morbidity and mortality in CVID and is believed to be the result of dysregulated B-cell function.⁴⁴ Because of the heterogeneity of clinical features, diagnosis is difficult and may be delayed for several years. The advent of new diagnostic techniques will likely improve outcomes.⁴²

Some defects may involve a particular class of antibody, such as selective IgA deficiency, in which only IgA is suppressed. It is the most prevalent of the selective antibody deficiencies and is defined as a decreased serum IgA level lower than 7 mg/dL in individuals older than 4 years with normal levels of IgM and IgG in serum and exclusion of other causes of hypogammaglobulinemia. Selective IgA deficiency occurs in 1 in 700 to 1 in 400 individuals, and familial inheritance occurs in approximately 20% of cases. There is an increased incidence of common variable immune deficiency and transient hypogammaglobulinemia of infancy among family members of those with selective IgA deficiency. It results from defects in the process of IgA class switch, production and secretion of IgA, and long-term survival of IgA-switched memory B cells and plasma cells.45 Many individuals are asymptomatic, although others have a history of recurring sinus, joint, and pulmonary infections.⁴¹ Some have gastrointestinal infection such as chronic intestinal candidiasis (infection with C. albicans). Complications of IgA deficiency include severe allergic disease and autoimmune diseases. Some individuals are at risk for life-threatening allergic reactions when they receive blood products that contain some IgA. This is thought to be due to IgG (or possibly IgE) anti-IgA antibodies, which may be found in some IgA-deficient individuals. Management includes treatment of infections and allergic reactions, but no specific treatment for this immunodeficiency is currently available.

Deficiencies in certain subclasses of antibody, particularly IgG2 (IgG subclass deficiency), may result from a defect in switch to a particular subclass constant region. A reduced level of IgG2 results in an inability to adequately attack polysaccharide antigens on the surface of encapsulated bacteria. Low levels of IgG2 therefore are responsible for recurrent risk for pneumonias caused by these bacteria. Management with IVIG reduces the number of infections.46

Bruton agammaglobulinemia (X-linked agammaglobulinemia) is caused by blocked development of mature B cells in bone marrow. It results from mutations of genes responsible for the synthesis of Bruton tyrosine kinase (BTK). An absence of BTK causes absent precursor B-cell differentiation in the bone marrow and severe B-cell deficiency (<2%).47 There is an associated inability to generate plasma cells and antibodies of all classes (panhypogammaglobulinemia). B-lineage cells in all organs are affected resulting in reduced sizes of lymph nodes and tonsils. Encapsulated bacterial infections are common. Nearly 85% of affected individuals develop infections early in life including otitis media, skin infection, sepsis, sinusitis, acute gastroenteritis, cervical lymphadenitis, epididymitis, meningitis, osteomyelitis, urinary tract infection, and encephalitis. Treatment consists of replacement immunoglobulin and prophylactic antibiotics to prevent infections.