Abstract
In this article we describe three infants who suffered from a disorder characterized by splenomegaly, anemia, and severe infections beginning during the first months of life. Immunologic studies revealed agammaglobulinemia. However, normal numbers of lymphocytes and lymphocyte subsets were present in peripheral blood, and lymphocyte proliferation in responses to mitogenic stimulation in vitro was normal. Histologic and immunohistologic studies performed in one of the patients revealed lack of secondary follicles and follicular dendritic cells in lymphoid tissues and absence of plasma cells in the intestinal lamina propria. Similar findings have been observed in the hyper-IgM syndrome. However, these patients can be distinguished from currently recognized genetic variants of hyper-IgM syndrome on the basis of their clinical and histologic features, together with information obtained from DNA sequence analysis. Thus, their condition is likely to represent a novel form of primary immune deficiency with features of hyper-IgM syndrome.
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REFERENCES
Nieuwenhuis P, Opstelten D, Gulbranson-Judge A, Casamayor-Palleja M, MacLennan IC: Functional anatomy of germinal centers. Am J Anat 170(3):421–435, 1984
MacLennan IC: Germinal centers. Annu Rev Immunol 12:117–139, 1994
Hess J, Laumen H, Muller KB, Wirth T: Molecular genetics of the germinal center reaction. J Cell Physiol 177(4):525–534, 1998
Measurement of proliferative responses of cultured lymphocytes. In Current Protocols in Immunology, J Coligan (ed). New York, 1999, pp
Villa A, Notarangelo LD, Di Santo JP, et al.: Organization of the human CD40L gene: Implications for molecular defects in X chromosome-linked hyper-IgM syndrome and prenatal diagnosis. Proc Natl Acad Sci USA 91(6):2110–2114, 1994
Reith W, Steimle V, Lisowska-Grospierre B, Fischer A, Mach B: Molecular basis of major histocompatibility complex class II deficiency. In Primary Immunodeficiency Diseases: A Molecular and Genetic Approach, HD Ochs, ECI Smith, J Puck (eds). New York, Oxford University Press, 1999, 167–180
Anderson DC, Schmalsteig FC, Finegold MJ, et al.: The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency: Their quantitative definition and relation to leukocyte dysfunction and clinical features. J Infect Dis 152(4):668–689, 1985
Barzanji AJ, Emery JL: Quantitative study of the lymphatic tissue and germinal centres in the spleen in infants dying from expected and unexpected causes (cot deaths). Histopathology 1(6):445–449, 1977
Levy J, Espanol-Boren T, Thomas C, et al.: Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr 131(1 Pt 1):47–54, 1997
DiSanto JP, Bonnefoy JY, Gauchat JF, Fischer A, de Saint Basile G: CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM. Nature 361(6412):541–543, 1993
Aruffo A, Farrington M, Hollenbaugh D, et al.: The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell 72(2):291–300, 1993
Allen RC, Armitage RJ, Conley ME, et al.: CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science 259(5097):990–993, 1993
Korthauer U, Graf D, Mages HW, et al.: Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature 361(6412):539–541, 1993
Lederman S, Yellin MJ, Cleary AM, et al.: T-BAM/CD40-L on helper T lymphocytes augments lymphokine-induced B cell Ig isotype switch recombination and rescues B cells from programmed cell death. J Immunol 152(5):2163–2171, 1994
Hong R, Schubert WK, Perrin EV, West CD: Antibody deficiency syndrome associated with beta-2 macroglobulinemia. J Pediatr 61:831–842, 1962
Facchetti F, Appiani C, Salvi L, Levy J, Notarangelo LD: Immunohistologic analysis of ineffective CD40-CD40 ligand interaction in lymphoid tissues from patients with X-linked immunodeficiency with hyper-IgM. Abortive germinal center cell reaction and severe depletion of follicular dendritic cells. J Immunol 154(12):6624–6633, 1995
Flores-Romo L, Bjorck P, Duvert V, van Kooten C, Saeland S, Banchereau J: CD40 ligation on human cord blood CD34+ hematopoietic progenitors induces their proliferation and differentiation into functional dendritic cells. J Exp Med 185(2):341–349, 1997
Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G: Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med 184(2):747–752, 1996
Jain A, Atkinson TP, Lipsky PE, Slater JE, Nelson DL, Strober W: Defects of T-cell effector function and post-thymic maturation in X-linked hyper-IgM syndrome. J Clin Invest 103(8):1151–1158, 1999
Ferrari S, Giliani S, Insalaco A, et al.: Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci USA 98(22):12614–12619, 2001
McHeyzer-Williams LJ, Driver DJ, McHeyzer-Williams MG: Germinal center reaction. Curr Opin Hematol 8(1):52–59, 2001
Schneider P, Takatsuka H, Wilson A, et al.: Maturation of marginal zone and follicular B cells requires B cell activating factor of the tumor necrosis factor family and is independent of B cell maturation antigen. J Exp Med 194(11):1691–1697, 2001
Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T: Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102(5):553–563, 2000
Revy P, Muto T, Levy Y, et al.: Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyper-IgM syndrome (HIGM2). Cell 102(5):565–575, 2000
Minegishi Y, Lavoie A, Cunningham-Rundles C, et al.: Mutations in activation-induced cytidine deaminase in patients with hyper IgM syndrome. Clin Immunol 97(3):203–210, 2000
Zonana J, Elder ME, Schneider LC, et al.: A novel X-linked disorder of immune deficiency and hypohydrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet 67(6):1555–1562, 2000
Doffinger R, Smahi A, Bessia C, et al.: X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet 27(3):277–285, 2001
Jain A, Ma CA, Liu S, Brown M, Cohen J, Strober W: Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol 2(3):223–228, 2001
Calderhead DM, Kosaka Y, Manning EM, Noelle RJ: CD40– CD154 interactions in B-cell signaling. Curr Top Microbiol Immunol 245(2):73–99, 2000
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Eisenstein, E.M., Aker, M., Savoldi, G. et al. A Primary Immunodeficiency Disorder Associated with Absence of Lymphoid Germinal Centers. J Clin Immunol 22, 297–305 (2002). https://doi.org/10.1023/A:1019978122881
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DOI: https://doi.org/10.1023/A:1019978122881