Most clinicians associate primary immunodeficiency disorders (PIDDs) with susceptibility to frequent or severe infections. It is less commonly recognized, however, that PIDDs are frequently associated with autoimmune or rheumatologic manifestations. This review provides a synopsis of the rheumatic manifestations associated with immunodeficiencies in each of the major compartments of the immune system.
Primary immunodeficiencies have traditionally been described in patients with recurrent, severe, or unusual infections. Before the broad availability of effective antibiotics and ready access to safe, plentiful immunoglobulin preparations, patients often succumbed to infections at an early age. As patients began to survive longer, the conundrum of autoimmunity associated with immunodeficiency became apparent; that is, why would an immune system that is incapable of effective responses to foreign antigens seemingly be capable of responding to host antigens and causing autoimmunity? Over time, more of the molecular and cellular mechanisms that underlie this autoimmunity have come to be understood, but many questions remain. As new genetic defects have been identified in association with immunodeficiency, it has become clear that autoimmunity or autoinflammation is the primary clinical manifestation of some disorders.
Prevalence of primary immunodeficiency disorders
In the absence of uniform, population-based programs that screen for all types of immunodeficiency, the actual incidence and prevalence of primary immunodeficiency disorders (PIDDs) is not clear. A recent randomized survey of 10,000 US households, however, estimated the prevalence of diagnosed PIDDs at approximately 1:1200 individuals. Blood bank studies evaluating donors for the most common immunodeficiency, selective IgA deficiency, have estimated an even higher prevalence (1:333 individuals among US donors). Many of these are asymptomatic from the standpoint of recurrent or severe infections, but there is significant evidence that patients with selective IgA deficiency are at increased risk for autoimmunity.
The 4 major compartments of the immune system
The body’s natural defenses against pathogens include a network of physical barriers (eg, skin and mucosal surfaces), immune cells (eg, lymphocytes and phagocytes), and soluble mediators (eg, complement, antibodies, and cytokines). Trying to remember and consider all these pieces can be daunting to busy clinicians so there is value in using a framework of 4 major compartments when thinking about and evaluating patients. The 4 major compartments are complement, phagocytes, B cells, and T cells ( Fig. 1 ). The Complement and phagocyte compartments together make up the majority of the immune system that is referred to as innate . The innate immune system mounts rapid responses to infectious organisms by recognizing patterns of molecules or groups of molecules that are present on pathogens but typically not on human cells. Each time a particular pathogen is encountered, the components of the innate immune system respond but do so in the same way each time because they are unable to adapt or improve their response. In contrast, the B-cell and T-cell compartments make up the adaptive portion of the immune system. The adaptive immune system has the ability to adapt and change each time it encounters a pathogen. This adaptability makes it possible to generate memory responses. Because of the time required to modify the response to each individual pathogen, the adaptive system typically takes on a major role in fighting pathogens after the innate system has already begun its response.
Together, the innate and adaptive systems work to maintain normal host function and resistance to infection. Disruption of any part of this intricate network can result in increased numbers of infections, susceptibility to specific pathogens, or autoimmunity. The pattern of infections, clinical symptoms, and laboratory abnormalities differs depending on which part of the immune system is affected and can provide important clues to the diagnosis in each individual case. Because some deficiencies can be rapidly fatal whereas others are mild, making a timely and accurate diagnosis is critical to providing appropriate clinical care. Clinical manifestations that are typical of immunodeficiencies in each of the immune compartments are described in Table 1 .
| Complement | Phagocytes | B Cell | T Cell |
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| Infections | |||
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| Autoimmunity | |||
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| Screening tests | |||
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The 4 major compartments of the immune system
The body’s natural defenses against pathogens include a network of physical barriers (eg, skin and mucosal surfaces), immune cells (eg, lymphocytes and phagocytes), and soluble mediators (eg, complement, antibodies, and cytokines). Trying to remember and consider all these pieces can be daunting to busy clinicians so there is value in using a framework of 4 major compartments when thinking about and evaluating patients. The 4 major compartments are complement, phagocytes, B cells, and T cells ( Fig. 1 ). The Complement and phagocyte compartments together make up the majority of the immune system that is referred to as innate . The innate immune system mounts rapid responses to infectious organisms by recognizing patterns of molecules or groups of molecules that are present on pathogens but typically not on human cells. Each time a particular pathogen is encountered, the components of the innate immune system respond but do so in the same way each time because they are unable to adapt or improve their response. In contrast, the B-cell and T-cell compartments make up the adaptive portion of the immune system. The adaptive immune system has the ability to adapt and change each time it encounters a pathogen. This adaptability makes it possible to generate memory responses. Because of the time required to modify the response to each individual pathogen, the adaptive system typically takes on a major role in fighting pathogens after the innate system has already begun its response.
Together, the innate and adaptive systems work to maintain normal host function and resistance to infection. Disruption of any part of this intricate network can result in increased numbers of infections, susceptibility to specific pathogens, or autoimmunity. The pattern of infections, clinical symptoms, and laboratory abnormalities differs depending on which part of the immune system is affected and can provide important clues to the diagnosis in each individual case. Because some deficiencies can be rapidly fatal whereas others are mild, making a timely and accurate diagnosis is critical to providing appropriate clinical care. Clinical manifestations that are typical of immunodeficiencies in each of the immune compartments are described in Table 1 .
| Complement | Phagocytes | B Cell | T Cell |
|---|---|---|---|
| Infections | |||
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| Autoimmunity | |||
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| Screening tests | |||
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Immunodeficiencies by compartment
Disorders of the Complement Compartment
Overview
The complement system consists of a series of more than 20 plasma proteins that are activated on encountering immune complexes or pathogens. Activation of the complement system initiates a cascade of protein cleavage events that produce active complement protein fragments that opsonize bacteria, attract immune cells, increase blood flow, and initiate formation of the membrane attack complex (consisting of the terminal complement components, C5, C6, C7, C8, and C9) on the surface of target cells ( Fig. 2 ). The complement cascade is activated via 3 major pathways: the classical pathway, initiated by antigen/antibody complexes; the alternative pathway, activated directly by bacterial cell wall components; and the lectin pathway, activated by mannose residues on the surface of pathogens. Under normal conditions, complement is continually activated at a low level in response to pathogens or fragments of pathogens encountered in the environment. Were it not for a group of complement regulatory proteins (factor H, factor I, and membrane cofactor protein [MCP]) that restrain complement activation at the level of C3, there would be rampant, continual activation of complement.
Complement deficiencies make up only a fraction (approximately 2%) of al primary immunodeficiencies but absence or dysfunction of only 1 of the more than 20 complement proteins can cause defective activation of the entire complement cascade. The proteins most often affected are C2, C3, and C4. Table 2 summarizes key clinical features of various complement defects but, in general, deficiencies of early complement components (C1–C4) in the classical pathway are associated with recurrent, invasive infections with encapsulated organisms (in particular, sepsis with organisms, such as Streptococcus pneumoniae ). Patients with defects in late complement components involved in formation of the membrane attack complex (C5–C9) typically present with neisserial infections. Defects of complement regulatory proteins are generally associated with familial hemolytic uremic syndrome (HUS) and age-related macular degeneration. The clinical symptoms of major complement disorders are outlined in Table 2 .
| Deficiency | Clinical Presentation | Testing |
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| C1–C4 (early) |
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| C5–C9 (late) |
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| Factor H Factor I MCP |
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Rheumatologic disease associated with defects in the complement compartment
Systemic lupus erythematosus
In addition to infection, patients with deficiency of early components of the classical complement pathway often present with symptoms of systemic lupus erythematosus (SLE) or a lupus-like glomerulonephritis. The reported prevalence of SLE is 93% with C1q deficiency, 57% with C1r/s deficiency, 75% with C4 deficiency, 32% to 33% with C2 deficiency, and 10% with C3 deficiency. Among these, C2 deficiency is most common, with an estimated incidence of 1 in 20,000. The mechanism behind the association between SLE and complement deficiency is thought to relate to the role that complement (in particular C1q) plays in binding to apoptotic cells and clearing them from the body. In the absence of C1q binding, dead and dying cells take longer to be cleared, thereby inducing inflammation that leads to the generation of autoantibodies such as anti-double-stranded DNA antibodies.
Screening for complement deficiency in the classical pathway typically involves performing a 50% complement hemolytic activity test (CH50) as well as evaluating the levels of specific complement components, including C2, C3, and C4. The CH50 is often moderately low in patients with active lupus of various causes; however, in patients with true complement deficiency, the CH50 is typically near zero.
Hemolytic uremic syndrome
Atypical HUS has now been linked to several defects in complement components, in particular those involved in regulation of complement activation, including factor H, factor I, and MCP. The recommended screening approach in patients with atypical HUS is to measure the levels of C3, C4, factor H, factor I, and MCP. This testing can be followed by gene sequencing to identify the specific genetic defect.
Disorders of the Phagocyte Compartment
Overview
One of the major roles of phagocytic cells (neutrophils, macrophages, and dendritic cells) is to continuously survey the body for infection. Infectious organisms in the tissues induce expression of adhesion molecules on the surface of nearby vascular endothelial cells. These adhesion receptors stop neutrophils that are rolling down the wall of the vessel, causing them to migrate out into the tissues toward the site of the infection where they begin to ingest both opsonized and nonopsonized pathogens and debris. The ingested material is degraded and fragments of digested proteins are loaded into MHC class II molecules that are presented at the cell surface where they can be recognized by cells of the adaptive immune system. In addition to destroying pathogens, phagocytes play a major role in clearing cellular debris, including dead and dying cells, from the body. As a result, patients with phagocyte deficiencies often exhibit poor wound healing.
Phagocyte disorders can be classified in 3 different groups: (1) absence of particular phagocyte subsets (congenital neutropenia or monocytopenia), (2) defective phagocyte migration (leukocyte adhesion deficiency), and (3) inability of phagocytes to process or degrade organisms that have been ingested. In general, symptoms of phagocytic disorders include recurrent skin or soft tissue abscesses, lymphadenitis, pneumonia, hepatic abscesses, inflammatory bowel disease, and gingivitis. The clinical symptoms of major phagocytic disorders are outlined in Table 3 .
