Chapter 78: Classification and Clinical Manifestations of Lymphocyte and Plasma Cell Disorders

Lymphocyte and plasma cell disorders can be classified into three major groups (Table 78–1). The first group, listed under “primary disorders,” is composed of lymphocyte disorders caused by intrinsic defects in lymphoid cells that result in functional abnormalities of marrow-derived (B) lymphocytes, thymic-derived (T) lymphocytes, combined T and B (impaired humoral and cellular immunity), or natural killer (NK) cells. These disorders primarily result from inborn errors in lymphocyte metabolism (Chaps. 73 to 77 and 80) and/or receptor–ligand expression (Chaps. 17 and 80). The second group, listed under “acquired disorders,” consists of disorders caused by factors extrinsic to lymphocytes resulting in immune dysfunction. These conditions most commonly result from infection with viruses, or other cellular pathogens (Chaps. 79, 81, and 82), but they also may be caused by bacteria, drugs or systemic disease of nonlymphoid cells. The third group of diseases is composed of preneoplastic and neoplastic lymphocyte disorders and is discussed in detail in Chap. 90.

Some categories of lymphocyte and plasma cell disorders may be difficult to distinguish clinically because lymphocyte disorders can have many clinical manifestations that are not restricted to cells of the immune system and disparate disorders can have similar clinical manifestations, with any one disorder associated with a diverse array of clinical pathologies.

In some cases, the classification of lymphocyte disorders is influenced by the manifestations of the disease. For example, autoimmune hemolytic disease (Chap. 54) and autoimmune thrombocytopenia (Chap. 117) are caused by inappropriate secretion of autoantibodies by B lymphocytes. The blood cell that is coated with autoantibody presumably is normal, yet we classify the disease that can result from hemolytic autoantibodies as an acquired hemolytic anemia because that aspect of the disease is more visible and better understood than is the inappropriate synthesis of antierythrocyte antibody by the disturbed lymphocyte population(s). These disorders are not considered here.

Many diseases, especially infection (e.g., tuberculous adenitis), inflammatory states (e.g., rheumatoid arthritis), autoimmune disease (e.g., systemic lupus erythematosus), and metastatic carcinoma can involve lymph nodes or the spleen as a secondary alteration. These disorders also may be associated with abnormal production of antibodies, such as those resulting in the lupus anticoagulant (Chap. 131). These disorders also are not considered here because the primary disease is not generally considered a lymphocyte disorder.

B LYMPHOCYTE DISORDERS

Immunoglobulin Deficiency

The clinical manifestations of B-lymphocyte disorders include the consequences of B-lymphocyte deficiency, dysfunction, or malignant transformation. The manifestations may consist of a specific deficiency of one of the immunoglobulin (Ig) isotypes or of several or all Ig molecules (panhypogammaglobulinemia; see Chap. 75). Inability to synthesize or secrete antibodies impairs the clearance of pathogens because of the inability to opsonize microorganisms for phagocytosis, resulting in immune dysregulation and dysfunction (Chap. 80).

Abnormal Immunoglobulin Production

Primary defect in the B-cell clone or expansion of a clone in response to chronic antigen stimulation can result in excess production of Ig that in turn produces a monoclonal gammopathy (Chap. 106). Monoclonal gammopathy can result in B-cell neoplastic disease, such as plasma cell myeloma (Chap. 107), Waldenström macroglobulinemia (Chap. 109) or chronic lymphocytic leukemia (Chap. 92). Production of abnormal Ig molecules or Ig fragments can also be seen in association with chronic infection, leading to development of Ig heavy-chain disease (Chap. 110). Deposition of Ig or Ig fragments can contribute to primary amyloid formation (Chap. 108). Reactivity of the Ig with self-antigen(s), such as those found on the red cell membrane (Chap. 54), can result in systemic autoimmune disease.

T LYMPHOCYTE DISORDERS

Impaired Immunoregulation

The clinical manifestations of deficiencies or excesses of T-lymphocytes depend on the subset of T-lymphocytes involved. Delayed hypersensitivity normally is mediated by CD4+ helper T cells (Th cells) and, more specifically, Th1-type cells (Chap. 76). A deficit or functional disturbance in these T-cells can impair the cellular immune response to mycobacteria, Listeria, Brucella, fungi, or other intracellular organisms associated with formation of immune granulomas. Th2-type CD4+ Th cells, on the other hand, appear better suited to induce B-cell responses to antigen and direct the immune response against parasitic infestations (Chap. 76). Deficiency or defects in CD4+ regulator T cells (T_REGs) can result in autoimmune disease, whereas depletion or deficiency of Th17 cells can result in impaired resistance to opportunistic infection (Chap. 76). Depletion of CD4+ T cells in patients infected with human immunodeficiency virus accounts in large part for the acquired immune deficiency that develops in patients infected with the virus (Chap. 81).

T lymphocytes within a marrow allograft are responsible for initiation of the graft-versus-host disease (GVHD) (Chap. 23). Acute GVHD can lead to severe dermatitis, gastroenteritis, and hepatitis. Chronic GVHD can encompass a collage of connective tissue diseases, such as scleroderma, xerophthalmia, xerostomia, and pulmonary insufficiency, specifically bronchiolitis obliterans. Eosinophilia, hypergammaglobulinemia, development of autoantibodies, and plasmacytosis can occur. Infection with classic or opportunistic pathogens is a common complication of both acute and chronic GVHD. A similar qualitative reaction, albeit more limited, is seen in mononucleosis resulting from Epstein-Barr virus infection (Chap. 82).

Combined T- and B-cell deficiency and dysfunction can result in heterogeneous group of disorders that affect both cellular and humoral immunity. The disorder can be severe (severe combined immune deficiency [SCID]) or mild depending on whether the defect is partial (hypomorphic defects) or complete (null or amorphic defects). Complete defects can result in early death, typically during the first year of life, from uncontrolled infection. An extreme form of SCID is the T-cell–negative, B-cell–negative, NK-cell–positive phenotype with children presenting early in life with severe infections, failure to thrive, and low-to-absent T-and B-cell numbers and function. Advances in gene therapy and allogeneic stem cell transplantation offer hope in some cases (Chap. 80).

Chronic NK cell lymphocytosis is a rare proliferative disorder that can be distinguished from NK cell leukemia and lymphoma by its indolent nature (Chap. 77). Patients typically have neutropenia, anemia, vasculitic syndromes, fever of unknown origin, constitutional symptoms, cutaneous lesions and autoimmune disorders, including rheumatoid arthritis, Sjögren syndrome, and/or polymyalgia rheumatica. Studies seeking to define this condition as a clonal disorder using X-linked gene analysis have not yielded consistent findings (Chap. 77).