CHAPTER 86 CLASSIFICATION AND CLINICAL MANIFESTATIONS OF LYMPHOCYTE AND PLASMA CELL DISORDERS
CHAPTER 86 CLASSIFICATION AND CLINICAL MANIFESTATIONS OF LYMPHOCYTE AND PLASMA CELL DISORDERS
THOMAS J. KIPPS
This chapter outlines the major categories of lymphocyte and plasma cell disorders. Such disorders can be sorted into three main groups. The first is comprised of diseases caused by defects that are intrinsic to lymphoid cells. The second is caused by disorders that result from factors extrinsic to lymphoid cells. The third is comprised of disorders caused by neoplastic or preneoplastic lymphoid cells and is outlined in Chap. 96. While the clinical manifestations of diseases in any one of these three groups may be difficult to distinguish, this grouping can provide a framework with which to proceed in evaluating patients with known or suspected lymphocyte disorders. This chapter introduces this framework and presents a road map to the chapters in the text that discuss each of these disorders in greater detail.
Lymphocyte and plasma cell disorders can be classified into three major groups. The first group is comprised of lymphocyte disorders that are due to intrinsic defects in lymphoid cells that result in functional abnormalities of marrow-derived (B) lymphocytes, thymic-derived (T) lymphocytes, or both (impaired humoral and cellular immunity) (Table 86-1). These disorders primarily are due to inborn errors in lymphocyte metabolism (see Chap. 81 and Chap. 88) and/or receptor/ligand expression (see Chap. 15 and Chap. 88). These are grouped together as “primary disorders” in Table 86-1. Next are disorders that are caused by factors extrinsic to lymphocytes resulting in immune dysfunction. These conditions most commonly are the result of infection with viruses or other cellular pathogens (see Chap. 87, Chap. 89, and Chap. 90) but also may be caused by drugs or systemic disease of nonlymphoid cells. These disorders are listed as “acquired disorders” in Table 86-1. The third group of diseases are comprised of preneoplastic and neoplastic lymphocyte disorders (see Chap. 96).
TABLE 86-1 CLASSIFICATION OF DISORDERS OF LYMPHOCYTES AND PLASMA CELLS
Different categories of lymphocyte and plasma cell disorders may be difficult to distinguish clinically. For one, lymphocyte disorders can have many clinical manifestations that are not restricted to cells of the immune system. Also, disparate disorders can have similar clinical manifestations, and any one disorder may be associated with a diverse array of clinical pathologies.
In some cases, however, the classification of lymphocyte disorders is influenced by the manifestations of the disease. For example, autoimmune hemolytic disease (see Chap. 55, Chap. 56 and Chap. 57) and autoimmune thrombocytopenia (see Chap. 117) are caused by the inappropriate secretion of autoantibodies by lymphocytes. The blood cell that is coated with autoantibody is presumably normal, yet we classify the disease that can result from hemolytic autoantibodies as an acquired hemolytic anemia. This is 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.
In addition, many diseases, especially infection (e.g., tuberculous adenitis), inflammatory states (e.g., rheumatoid arthritis), autoimmune disease (e.g., systemic lupus erythematosus), or 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 (see Chap. 128). These disorders also are not considered here because the primary disease is not generally considered a lymphocyte disorder per se.
The clinical manifestations of B-lymphocyte disorders include the consequences of B-lymphocyte deficiency, dysfunction, or malignant transformation and may consist of a specific deficiency of one of the immunoglobulin isotypes or of several or all normal Ig molecules (panhypogammaglobulinemia) (see Chap. 83). Inability to synthesize or secrete antibodies impairs the clearance of pathogens due to the inability to opsonize microorganisms for phagocytosis, resulting in immune deficiency (see Chap. 88).
ABNORMAL IMMUNOGLOBULIN PRODUCTION
Excess production of immunoglobulin by a clone of B cells can result in essential monoclonal gammopathy (see Chap. 105). This could result from a primary defect in the B-cell clone or expansion of a clone in response to chronic antigen stimulation. Essential monoclonal gammopathy could be a harbinger for development of B-cell neoplastic disease, such as plasma cell myeloma (see Chap. 106) or Waldenström macroglobulinemia (see Chap. 108). Production of abnormal immunoglobulin molecules or immunoglobulin fragments also can be seen associated with chronic infection, leading to development of immunoglobulin heavy-chain disease (see Chap. 109). Deposition of immunoglobulin or immunoglobulin fragments can contribute to formation of amyloid (see Chap. 107). Reactivity of the immunoglobulin with self-antigen(s), such as those found on the red cell membrane (see Chap. 55 and Chap. 56), can result in systemic autoimmune disease.
The clinical manifestations of deficiencies or excesses of T lymphocytes depend on the subset of T lymphocytes involved. For example, delayed hypersensitivity normally is mediated by CD4-positive helper T cells (TH cells) and more specifically TH1-type cells (see Chap. 84). 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 the formation of immune granulomas. TH2-type CD4-positive helper T cells, on the other hand, appear better suited to induce B-cell responses to antigen and direct the immune response against parasitic infestations (see Chap. 84). Depletion of CD4 T cells in patients infected with human immunodeficiency virus accounts in large part to the acquired immune deficiency that develops in patients infected with this virus (see Chap. 89).
T lymphocytes within a marrow allograft are responsible for initiation of the graft-versus-host reaction (see Chap. 18). The acute form of the reaction can lead to severe dermatitis, gastroenteritis, and hepatitis. The chronic syndrome simulates a collage of vascular diseases, such as scleroderma, xerophthalmia, xerostomia, and pulmonary insufficiency. Eosinophilia, hypergammaglobulinemia, development of autoantibodies, and plasmacytosis also can occur. Infection with classical or opportunistic pathogens is a common complication of both acute and chronic graft-versus-host disease. A similar qualitative reaction, albeit more limited, is seen in mononucleosis that results from Epstein-Barr virus infection (see Chap. 90).
Conley ME, Park CL, Douglas SD: Childhood common variable immunodeficiency with autoimmune disease. J Pediatr 108:915, 1986.
Buckley RH: Immunodeficiency diseases. JAMA 268:2797, 1992.
Kyrtsonis MC, Mouzaki A, Maniatis A: Mechanisms of polyclonal hypogammaglobulinaemia in multiple myeloma (MM). Med Oncol 16:73, 1999.
Hodgson HJ: Immunological aspects of inflammatory bowel diseases of the human gut. Agents Actions Spec No: C27, 1992.
Smith CI, Bäckesjö CM, Berglöf A, et al: X-linked agammaglobulinemia: lack of mature B lineage cells caused by mutations in the Btk kinase. Springer Semin Immunopathol 19:369, 1998.
Rawlings DJ: Bruton’s tyrosine kinase controls a sustained calcium signal essential for B lineage development and function. Clin Immunol 91:243, 1999.
Nonoyama S: Recent advances in the diagnosis of X-linked agamma-globulinemia [editorial]. Intern Med 38:687, 1999.
Auerbach AD, Verlander PC: Disorders of DNA replication and repair. Curr Opin Pediatr 9:600, 1997.
Chakraverty RK, Hickson ID: Defending genome integrity during DNA replication: a proposed role for RecQ family helicases. Bioessays 21:286, 1999.
Callard RE, Smith SH, Matthews DJ: Regulation of human B cell growth and differentiation: lessons from the primary immunodeficiencies. Chem Immunol 67:114, 1997.
Guill MF, Brown DA, Ochs HD, Pyun KH, Moffitt JE: IgM deficiency: clinical spectrum and immunologic assessment. Ann Allergy 62:547, 1989.
Sullivan KE: Recent advances in our understanding of Wiskott-Aldrich syndrome. Curr Opin Hematol 6:8, 1999.
Snapper SB, Rosen FS: The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization. Annu Rev Immunol 17:905, 1999.
Strober W, Sneller MC: IgA deficiency. Ann Allergy 66:363, 1991.
Collin P, Maki M, Keyrilainen O, Hallstrom O, Reunala T, Pasternack A: Selective IgA deficiency and coeliac disease. Scand J Gastroenterol 27:367, 1992.
Levenson T, Greenberger PA, Murphy R: Peripheral blood eosinophilia, hyperimmunoglobulinemia A and fatigue: possible complications following rupture of silicone breast implants. Ann Allergy Asthma Immunol 77:119, 1996.
Livneh A, Drenth JP, Klasen IS, et al: Familial Mediterranean fever and hyperimmunoglobulinemia D syndrome: two diseases with distinct clinical, serologic, and genetic features. J Rheumatol 24:1558, 1997.
Livneh A, Langevitz P: [Hyperimmunoglobulinemia D—a new periodic syndrome with features simulating familial Mediterranean fever]. Harefuah 131:283, 1996.
Leung DY, Geha RS: Clinical and immunologic aspects of the hyperimmunoglobulin E syndrome. Hematol Oncol Clin North Am 2:81, 1988.
Blanche P, Bachmeyer C, Buvry C, Sicard D: Hyperimmunoglobulinemia E syndrome in HIV infection. J Am Acad Dermatol 36:106, 1997.
Ramesh N, Seki M, Notarangelo LD, Geha RS: The hyper-IgM (HIM) syndrome. Springer Semin Immunopathol 19:383, 1998.
Notarangelo LD, Duse M, Ugazio AG: Immunodeficiency with hyper-IgM (HIM). Immunodefic Rev 3:101, 1992.
Fuleihan R, Ramesh N, Loh R, et al: Defective expression of the CD40 ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM. Proc Natl Acad Sci USA 90:2170, 1993.
Allen RC, Armitage RJ, Conley ME, et al: CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science 259:990, 1993.
Fischer A, Cavazzana-Calvo M, De Saint Basile G, et al: Naturally occurring primary deficiencies of the immune system. Annu Rev Immunol 15:93, 1997.
Makitie O, Kaitila I: Cartilage-hair hypoplasia—clinical manifestations in 108 Finnish patients. Eur J Pediatr 152:211, 1993.
Makitie O, Rajantie J, Kaitila I: Anaemia and macrocytosis—unrecognized features in cartilage-hair hypoplasia. Acta Paediatr 81:1026, 1992.
Hogg N, Stewart MP, Scarth SL, et al: A novel leukocyte adhesion deficiency caused by expressed but nonfunctional beta2 integrins Mac-1 and LFA-1. J Clin Invest 103:97, 1999.
Wright AH, Douglass WA, Taylor GM, et al: Molecular characterization of leukocyte adhesion deficiency in six patients. Eur J Immunol 25:717, 1995.
Lipnick RN, Iliopoulos A, Salata K, Hershey J, Melnick D, Tsokos GC: Leukocyte adhesion deficiency: report of a case and review of the literature. Clin Exp Rheumatol 14:95, 1996.
Demczuk S, Aurias A: DiGeorge syndrome and related syndromes associated with 22q11.2 deletions. A review. Ann Genet 38:59, 1995.
Hong R: The DiGeorge anomaly (CATCH 22, DiGeorge/velocardiofacial syndrome). Semin Hematol 35:282, 1998.
Harrison LF, Shearer WT: Evaluation and management of B and T cell abnormalities. Allergy Proc 12:25, 1991.
Frick H, Münger DM, Fauchère JC, Stallmach T: Hypoplastic thymus and T-cell reduction in EECUT syndrome. Am J Med Genet 69:65, 1997.
Fischer A, Malissen B: Natural and engineered disorders of lymphocyte development. Science 280:237, 1998.
Meyn MS: Ataxia-telangiectasia, cancer and the pathobiology of the ATM gene. Clin Genet 55:289, 1999.
Crawford TO: Ataxia telangiectasia. Semin Pediatr Neurol 5:287, 1998.
Datta U, Sehgal S, Kumar L, et al: Immune status in ataxia telangiectasia. Indian J Med Res 94:252, 1991.
Taylor AM, Jaspers NG, Gatti RA: Fifth International Workshop on Ataxia-Telangiectasia. Cancer Res 53:438, 1993.
Hershfield MS: Adenosine deaminase deficiency: clinical expression, molecular basis, and therapy. Semin Hematol 35:291, 1998.
Griscelli C, Lisowska-Grospierre B, Mach B: Combined immunodeficiency with defective expression in MHC class II genes. Immunodefic Rev 1:135, 1989.
Standen GR: Wiskott-Aldrich syndrome: a multidisciplinary disease. J Clin Pathol 44:979, 1991.
Inbal A, Avidor I, Nemesh L, Shaklai M: Persistent lymphocytosis: an unusual feature in sarcoidosis. Acta Haematol 74:184, 1985.
Barton AD: T-cell lymphocytosis associated with lymphocyte-rich thymoma. Cancer 80:1409, 1997.
Medeiros LJ, Bhagat SK, Naylor P, Fowler D, Jaffe ES, Stetler-Stevenson M: Malignant thymoma associated with T-cell lymphocytosis. A case report with immunophenotypic and gene rearrangement analysis. Arch Pathol Lab Med 117:279, 1993.
Trakatellis A, Dimitriadou A, Trakatelli M: Pyridoxine deficiency: new approaches in immunosuppression and chemotherapy. Postgrad Med J 73:617, 1997.
Gitlin D, Vawter G, Craig JM: Thymic alymphoplasia and congenital aleukocytosis. Pediatrics 33:184, 1964.
Elder ME: SCID due to ZAP-70 deficiency. J Pediatr Hematol Oncol 19:546, 1997.
Brown KA: Nonmalignant disorders of lymphocytes. Clin Lab Sci 10:329, 1997.
Kubic VL, Kubic PT, Brunning RD: The morphologic and immunophenotypic assessment of the lymphocytosis accompanying Bordetella pertussis infection. Am J Clin Pathol 95:809, 1991.
Drew WL, Lalezari JP: Cytomegalovirus: disease syndromes and treatment. Curr Clin Top Infect Dis 19:16, 1999.
Holcombe RF: Drug-induced granulocytopenia with natural killer lymphocytosis after renal transplantation. Acta Haematol 83:96, 1990.
Toft P, Tonnesen E, Svendsen P, Rasmussen JW, Christensen NJ: The redistribution of lymphocytes during adrenaline infusion. An in vivo study with radiolabelled cells. APMIS 100:593, 1992.
Peter J, Ray CG: Infectious mononucleosis. Pediatr Rev 19:276, 1998.
Zambello R, Semenzato G: Large granular lymphocytosis. Haematologica 83:936, 1998.
Greenberg MS: Herpesvirus infections. Dent Clin North Am 40:359, 1996.
Troussard X, Flandrin G: Chronic B-cell lymphocytosis with binucleated lymphocytes (LWBL): a review of 38 cases. Leuk Lymphoma 20:275, 1996.
Erffmeyer JE: Serum sickness. Ann Allergy 56:105, 1986.
Virella G: Immune complex diseases. Immunol Ser 50:395, 1990.
Saulsbury FT: B cell proliferation in acute infectious lymphocytosis. Pediatr Infect Dis J 6:1127, 1987.
Griffin G, Krishna S: Cytokines in infectious diseases. J R Coll Physicians Lond 32:195, 1998.
Gulle H, Schoel B, Chiplunkar S, Gangal S, Deo MG, Kaufmann SH: T-cell responses of leprosy patients and healthy contacts toward separated protein antigens of Mycobacterium leprae. Int J Lepr Other Mycobact Dis 60:44, 1992.
Walker KB, Butler R, Colston MJ: Role of Th-1 lymphocytes in the development of protective immunity against Mycobacterium leprae. Analysis of lymphocyte function by polymerase chain reaction detection of cytokine messenger RNA. J Immunol 148:1885, 1992.
Pande I, Sekharan NG, Kailash S, et al: Analysis of clinical and laboratory profile in Indian childhood systemic lupus erythematosus and its comparison with SLE in adults. Lupus 2:83, 1993.
Masson C, Perroux-Goummy L, Audran M: Felty’s syndrome, pseudo-felty’s syndrome, monoclonal or polyclonal CD3 lymphocytosis of undetermined significance. Rev Rhum Engl Ed 63:5, 1996.
Moller DR: Cells and cytokines involved in the pathogenesis of sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 16:24, 1999.
Daniele RP, Dauber JH, Rossman MD: Immunologic abnormalities in sarcoidosis. Ann Intern Med 92:406, 1980.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn