The immune system is a tightly regulated network that incorporates both innate and adaptive pathways. The genes regulating the innate system are coded in the germ line. The innate immune system is not antigen specific. The cells and soluble factors of the innate system have pattern recognition receptors (PRRs, such as toll-like receptors) to common motifs on pathogens and altered self-motifs. The motifs on pathogens are called pathogen-associated molecular patterns (PAMPs). Altered self-antigens include danger-associated molecular patterns (DAMPs) as found in heat shock protein, and apoptosis-associated molecular patterns (AAMPs) as found in ds DNA, RNP, and histones. This response is rapid and there is no memory of the encounter.

The receptors on the T and B cells of the adaptive immune system are antigen or epitope specific and clonally variable, and their diversity is derived from gene recombination. The cells retain memory of the encounter and on subsequent engagement with that antigen, the cells exhibit more rapid and robust responses.

The immune network is tightly regulated by cells and cytokines, and a derangement in this immune homeostasis can result in immune response to self-antigens as in autoimmunity (failure of self-tolerance), or failure to recognize pathogens and eliminate them as occurs in immunodeficiency syndromes (failure of immunity). The following 2 groups of disorders are the focus of this chapter: the autoimmune diseases involving the connective tissue and the immunodeficiency diseases.

Diseases in which immune responses to self-antigens occur in the context of a genetic predisposition to disease expression are called autoimmune diseases. Some involve organ-specific pathologic autoimmunity such as Hashimoto thyroiditis and celiac disease, and these are discussed in Chapters 22 and 15, respectively. The autoimmune disorders discussed in this chapter are systemic diseases with predominant involvement of the connective tissue, manifesting clinical features including inflammation of the joints, skin, muscles, and other soft tissues (see Tables 3–1 and 3–2 and Figure 3–1).

The immunodeficiency diseases are subdivided into the relatively rare primary and the more common secondary immunodeficiency diseases. Primary immunodeficiency diseases are a direct consequence of either structural or functional derangement in the immune network. Secondary immune deficiency is the manifestation of a primary infectious disease, such as HIV infection; a malignancy as seen in lymphoma and multiple myeloma; or exposure to a therapeutic regimen such as immunosuppression or radiation.

Systemic Lupus Erythematosus

Description

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, associated with the production of antibodies to a variety of nuclear and cytoplasmic antigens. The hallmark characteristic is the generation of antibodies to ds DNA. These antibodies complex to these self-antigens, and the ensuing immune complexes contribute to the inflammation in many organs, particularly the skin, joints, kidney, and, to a lesser extent, the cardiovascular and nervous systems, lung, and hemopoietic cells.

The disease is more common in women than in men and usually appears in early adulthood, although it is seen in children as well. It not only is more common in African Americans than in Caucasians but also has a more severe clinical phenotype with renal and vasculitic manifestations in African Americans.

The candidate genes associated with SLE include those coding for complement components C1q, C4A, C2, activating and inhibitory FcγR, interferon regulatory factor 5 (IRF5), TNF, MHC class II (DR2 and DR3), and programmed cell death PDCD1, among others.

Table 3–3 summarizes the laboratory evaluation of SLE and Table 3–4 lists the autoantibodies associated with SLE.

Diagnosis

According to the American Rheumatologic Association criteria for diagnosis of SLE, the diagnosis of SLE is made if 4 or more of the following 11 criteria are present at any time during the course of the disease:

Tests utilized in the initial evaluation and subsequent monitoring of patients with SLE are shown in Tables 3–3 and 3–4 and Figure 3–1.

Sjogren Syndrome

Description

Sjogren syndrome (SS) is a systemic connective tissue disease, more common in women than in men. Pathologically, it is an autoimmune exocrinopathy involving the lacrimal glands, salivary glands, and less often the pancreas. The immune inflammation of these glands contributes to the sicca syndrome, with dry eyes (keratoconjunctivitis) and dry mouth (xerostomia) as characteristic clinical features. The disease can be primary or secondary. The primary syndrome is characterized by dry eyes, dry mouth, decreased production of tears as tested by the Schirmer test, and a lip biopsy that demonstrates inflammation of the minor salivary glands. Serologically, patients with primary Sjogren show a positive ANA, positive SS-A (Ro), positive SS-B (La), and positive rheumatoid factor (RF) in the absence of another connective tissue disease. A prospective study of 80 patients with primary SS followed for a median of 7.5 years reported the following frequencies of clinical manifestations: a) keratoconjunctivitis sicca and/or xerostomia occurred in all patients and were the only disease manifestations in 31%; b) extraglandular involvement occurred in 25%; and c) non-Hodgkin lymphoma developed in 2.5%. Secondary SS is clinically similar to the primary disorder, but it is additionally associated with clinical and serologic features of another connective tissue disease, such as rheumatoid arthritis (RA) or scleroderma.

Diagnosis

The diagnostic features are revealed by tests that document the sicca features. The dry eyes are evaluated by the Schirmer test. This test is a measurement of tear flow over a 5-minute period. Filter paper is allowed to hang from the lateral inferior eyelid and the length of the paper that becomes wet is measured. This test is not reliable, as early in the disease there is excessive lacrimation giving a false-negative test. Demonstration of devitalized corneal epithelium due to keratoconjunctivitis is evaluated by rose Bengal or fluorescein stain. The most accurate test is the slit lamp examination of the cornea and conjunctiva. Tests for quantitating salivary secretion are not standardized and also are not specific to SS. Biopsy of the minor salivary gland in the lower lip demonstrating focal lymphocytic infiltration is a useful confirmatory test.

Table 3–5 summarizes the laboratory tests useful in diagnosis of both primary and secondary SS.

Systemic Sclerosis/Scleroderma

Description

Systemic sclerosis is characterized by excessive and widespread deposition of collagen in many organ systems of the body. The hallmark of this pathologic process is the deposition of altered collagen in the extracellular matrix. The disorder is characterized pathologically by 3 features: 1) tissue fibrosis; 2) a proliferative and occlusive vasculopathy of the small blood vessels; and 3) a specific autoimmune response associated with distinctive autoantibody profile.

The immunologic basis is not well understood, but an aberration in TGF-beta-mediated deposition of collagen has been observed. Antibodies to platelet-derived growth factor receptors have been incriminated in the development of fibrosis. Both the triggering event and genetic predisposition are not well defined. Although the common organ involved is the skin, the gastrointestinal tract, kidney, lung, and muscles are also affected as the disease progresses. Renal ischemia leading to hypertension escalates the complications of this disease. Preponderance in females is common.

Clinically there are 4 major subtypes described:

1. 
   

   Diffuse cutaneous scleroderma with widespread involvement of skin and visceral organs.

   
   
2. 
   

   Limited cutaneous scleroderma, in which the disease is limited to the digital extremities and face. CREST syndrome is a variant of this entity. The name is derived from its features—calcinosis, Raynaud syndrome, esophageal dysmotility, sclerodactyly, and telangiectasia.

   
   
3. 
   

   Localized scleroderma that affects primarily the skin of the forearms, the fingers, and later the systemic organs.

   
   
4. 
   

   Overlap syndromes with features of RA or muscle involvement.

Diagnosis

Ninety percent to 95% of all patients with scleroderma have a positive ANA test. The most common pattern is finely speckled, followed by centromeric and nucleolar patterns. The ANA activity is directed against DNA topoisomerase (also known as Scl-70). A definitive diagnosis is achieved when the characteristic clinical findings are accompanied by a positive ANA test, and often confirmed by an antibody directed to Scl-70 by ELISA.

Tables 3–6.1 and 3–6.2 summarize the laboratory evaluation for systemic sclerosis/scleroderma.

Inflammatory Muscle Diseases

Description

Inflammation of the muscle leading to injury and weakness is the basis of the 3 most common but distinct diseases in this category. They are dermatomyositis (DM), polymyositis (PM), and inclusion body myositis. These diseases are more common in women, and their etiology remains unknown, although immune mechanisms have been incriminated. DM may occur as a specific entity or be associated with scleroderma or mixed connective tissue disease. Rarely, it is a manifestation of a malignancy. Skin manifestations such as a heliotrope rash, the shawl sign, and Gottron papules are common in DM. Like DM, PM may also be associated with another connective tissue disease. In addition, it may be associated with viral, parasitic, or bacterial infections. DM is characterized by immune complex deposition in the vessels and is considered to be in part a complement-mediated vasculopathy. In contrast, PM appears to reflect direct T-cell-mediated muscle injury. Inclusion body myositis is a disease of older individuals and is not associated with malignancy. It is occasionally associated with another connective tissue disease.