Advertisement

Journal of Clinical Immunology

, Volume 34, Issue 6, pp 615–626 | Cite as

Ill-Defined Germinal Centers and Severely Reduced Plasma Cells are Histological Hallmarks of Lymphadenopathy in Patients with Common Variable Immunodeficiency

  • Susanne Unger
  • Maximilian Seidl
  • Annette Schmitt-Graeff
  • Joachim Böhm
  • Klaudia Schrenk
  • Claudia Wehr
  • Sigune Goldacker
  • Ruth Dräger
  • Barbara C. Gärtner
  • Paul Fisch
  • Martin Werner
  • Klaus Warnatz
Original Research

Abstract

Given the severely reduced numbers of circulating class-switched memory B cells and plasmablasts in patients with common variable immunodeficiency (CVID) the germinal center (GC) reaction as the source of both populations is expected to be disturbed in many CVID patients. Therefore immunohistochemical studies were performed on lymph node (LN) biopsies from ten CVID patients with benign lymphoproliferation. According to the Sander classification the majority of patients presented with reactive lymphoid hyperplasia (7/10), 6/10 showed granulomatous inflammation. All cases showed some normal GCs but in 9/10 these concurred to a varying degree with hyperplastic, ill-defined GCs in the same LN. The percentage of ill-defined GCs correlated significantly with the percentage of circulating CD21low B cells suggesting a common origin of both immune reactions. In 9/10 CVID LNs significantly higher numbers of infiltrating CD8+ T cells were found in GCs of CVID patients compared to controls, but no HHV-8 and only in 2/10 LNs EBV infection was detected. Class switched plasma cells (PCs) were severely reduced in 8/10 LNs and if present, rarely found in the medulla of the LN. Based on the presence of large GCs in all examined patients, the reduction of circulating memory B cells and PCs points towards a failure of GC output rather than GC formation in CVID patients with lymphadenopathy.

Keywords

Common variable immunodeficiency plasma cell CD8 T cell germinal center granuloma histology 

Notes

Acknowledgments

We would like to thank Mrs. Weinhold for excellent technical assistance.

Supplementary material

10875_2014_52_MOESM1_ESM.docx (15 kb)
Table S1 (DOCX 15 kb)
10875_2014_52_MOESM2_ESM.docx (15 kb)
Table S2 (DOCX 14 kb)
10875_2014_52_MOESM3_ESM.docx (16 kb)
Table S3 (DOCX 15 kb)

References

  1. 1.
    Warnatz K, Denz A, Drager R, Braun M, Groth C, Wolff-Vorbeck G, et al. Severe deficiency of switched memory B cells (CD27(+)IgM(−)IgD(−)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood. 2002;99(5):1544–51.PubMedCrossRefGoogle Scholar
  2. 2.
    DiSanto JP, Bonnefoy JY, Gauchat JF, Fischer A, de Saint BG. CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature. 1993;361(6412):541–3.PubMedCrossRefGoogle Scholar
  3. 3.
    Ferrari S, Giliani S, Insalaco A, Al-Ghonaium A, Soresina AR, Loubser M, et al. Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci U S A. 2001;98(22):12614–9.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Warnatz K, Bossaller L, Salzer U, Skrabl-Baumgartner A, Schwinger W, van der Burg M, et al. Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood. 2006;107(8):3045–52.PubMedCrossRefGoogle Scholar
  5. 5.
    Qi H, Cannons JL, Klauschen F, Schwartzberg PL, Germain RN. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature. 2008;455(7214):764–9.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Revy P, Muto T, Levy Y, Geissmann F, Plebani A, Sanal O, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell. 2000;102(5):565–75.PubMedCrossRefGoogle Scholar
  7. 7.
    Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2008;111(1):77–85.PubMedCrossRefGoogle Scholar
  8. 8.
    Sander CA, Medeiros LJ, Weiss LM, Yano T, Sneller MC, Jaffe ES. Lymphoproliferative lesions in patients with common variable immunodeficiency syndrome. Am J Surg Pathol. 1992;16(12):1170–82.PubMedCrossRefGoogle Scholar
  9. 9.
    Groth C, Drager R, Warnatz K, Wolff-Vorbeck G, Schmidt S, Eibel H, et al. Impaired up-regulation of CD70 and CD86 in naive (CD27-) B cells from patients with common variable immunodeficiency (CVID). Clin Exp Immunol. 2002;129(1):133–9.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Fischer MB, Hauber I, Eggenbauer H, Thon V, Vogel E, Schaffer E, et al. A defect in the early phase of T-cell receptor-mediated T-cell activation in patients with common variable immunodeficiency. Blood. 1994;84(12):4234–41.PubMedGoogle Scholar
  11. 11.
    Wheat WH, Cool CD, Morimoto Y, Rai PR, Kirkpatrick CH, Lindenbaum BA, et al. Possible role of human herpesvirus 8 in the lymphoproliferative disorders in common variable immunodeficiency. J Exp Med. 2005;202(4):479–84.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93(3):190–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Kojima M, Nakamura S, Itoh H, Motoori T, Sugihara S, Shinkai H, et al. Angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: a clinicopathological and immunohistochemical study of 10 cases. APMIS. 2001;109(10):699–706.PubMedCrossRefGoogle Scholar
  14. 14.
    Toccanier MF, Kapanci Y. Lymphadenopathy in drug addicts. A study of the distribution of T lymphocyte subsets in the lymph nodes. Virchows Archiv A, Pathological Anat Histopathol. 1985;406(2):149–63.CrossRefGoogle Scholar
  15. 15.
    O’Malley DPGT, Orazi A, Abbondanzo SL. General Reactive Conditions in Lymph Node and Spleen. In: O’Malley DPGT, Orazi A, Abbondanzo SL, editors. Atlas of Nontumor Pathology 7 Benign & Reactive Conditions Lymph Node & Spleen. 1st ed. Washington, DC: The American Registry of Pathology; 2009. p. 129–33.Google Scholar
  16. 16.
    Chan PK, Ng HK, Cheung JL, Cheng AF. Survey for the presence and distribution of human herpesvirus 8 in healthy brain. J Clin Microbiol. 2000;38(7):2772–3.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Warnatz K, Schlesier M. Flowcytometric phenotyping of common variable immunodeficiency. Cytometry B Clin Cytom. 2008;74(5):261–71.PubMedCrossRefGoogle Scholar
  18. 18.
    Chevalier N, Jarrossay D, Ho E, Avery DT, Ma CS, Yu D, et al. CXCR5 expressing human central memory CD4 T cells and their relevance for humoral immune responses. J Immunol. 2011;186(10):5556–68.PubMedCrossRefGoogle Scholar
  19. 19.
    Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011;34(1):108–21.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Ochtrop ML, Goldacker S, May AM, Rizzi M, Draeger R, Hauschke D, et al. T and B lymphocyte abnormalities in bone marrow biopsies of common variable immunodeficiency. Blood. 2011;118(2):309–18.PubMedCrossRefGoogle Scholar
  21. 21.
    Taubenheim N, von Hornung M, Durandy A, Warnatz K, Corcoran L, Peter HH, et al. Defined blocks in terminal plasma cell differentiation of common variable immunodeficiency patients. J Immunol. 2005;175(8):5498–503.PubMedCrossRefGoogle Scholar
  22. 22.
    Herbst EW, Armbruster M, Rump JA, Buscher HP, Peter HH. Intestinal B cell defects in common variable immunodeficiency. Clin Exp Immunol. 1994;95(2):215–21.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Scott LJ, Bryant A, Webster AD, Farrant J. Failure in IgA secretion by surface IgA-positive B cells in common variable immunodeficiency (CVID). Clin Exp Immunol. 1994;95(1):10–3.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Fossum S, Ford WL. The organization of cell populations within lymph nodes: their origin, life history and functional relationships. Histopathology. 1985;9(5):469–99.PubMedCrossRefGoogle Scholar
  25. 25.
    van der Valk P MC. The Lymph Nodes. In: Mills SE, editors. Histology for Pathologists. 3 ed. Philadelphia: Lippincott Williams and Wilkins; 2007. pp. 763–81.Google Scholar
  26. 26.
    Humpert ML, Pinto D, Jarrossay D, Thelen M. CXCR7 influences the migration of B cells during maturation. European journal of immunology. 2013.Google Scholar
  27. 27.
    Kojima M, Kashimura M, Itoh H, Noro M, Matsuda H, Tsukamoto N. Infectious mononucleosis lymphoadenitis showing histologic findings indistinguishable from toxoplasma lymphadenitis. A report of three cases. Pathol Res Pract. 2010;206(6):361–4.PubMedCrossRefGoogle Scholar
  28. 28.
    Gujral S, Gandhi JS, Valsangkar S, Shet TM, Epari S, Subramanian PG. Study of the morphological patterns and association of Epstein-Barr virus and human herpes virus 8 in acquired immunodeficiency deficiency syndrome-related reactive lymphadenopathy. Indian J Pathol Microbiol. 2010;53(4):723–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Turner RR, Levine AM, Gill PS, Parker JW, Meyer PR. Progressive histopathologic abnormalities in the persistent generalized lymphadenopathy syndrome. Am J Surg Pathol. 1987;11(8):625–32.PubMedCrossRefGoogle Scholar
  30. 30.
    Kojima M, Kitamoto Y, Shimizu K, Matsuda H, Masawa N. Tonsillar lesions of infectious mononucleosis resembling MALT type lymphoma. A report of two cases. Pathol Oncol Res: POR. 2008;14(4):489–92.PubMedCrossRefGoogle Scholar
  31. 31.
    Mrusek S, Marx A, Kummerle-Deschner J, Tzaribachev N, Enders A, Riede UN, et al. Development of granulomatous common variable immunodeficiency subsequent to infection with Toxoplasma gondii. Clin Exp Immunol. 2004;137(3):578–83.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Siim JC, Nissen NI. Toxoplasmosis acquisita lymphonodosa in a 62-year-old woman; isolation of Toxoplasma gondli from lymph node and muscle biopsies. Acta Pathol Microbiol Scand. 1958;43(3):298–304.PubMedCrossRefGoogle Scholar
  33. 33.
    Sheibani K, Fritz RM, Winberg CD, Burke JS, Rappaport H. “Monocytoid” cells in reactive follicular hyperplasia with and without multifocal histiocytic reactions: an immunohistochemical study of 21 cases including suspected cases of toxoplasmic lymphadenitis. Am J Clin Pathol. 1984;81(4):453–8.PubMedGoogle Scholar
  34. 34.
    Dargent JL, Haller A, Durdurez JP, Gennotte AF. Atypical hyperplasia of the marginal zone of B follicles in a polymorphic Epstein-Barr virus-associated lymphoproliferative disorder occurring in an adolescent with human immunodeficiency virus infection. Pediatr Dev Pathol: the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. 2009;12(1):59–62.CrossRefGoogle Scholar
  35. 35.
    Ree HJ, Kadin ME, Kikuchi M, Ko YH, Go JH, Suzumiya J, et al. Angioimmunoblastic lymphoma (AILD-type T-cell lymphoma) with hyperplastic germinal centers. Am J Surg Pathol. 1998;22(6):643–55.PubMedCrossRefGoogle Scholar
  36. 36.
    Ree HJ, Kadin ME, Kikuchi M, Ko YH, Suzumiya J, Go JH. Bcl-6 expression in reactive follicular hyperplasia, follicular lymphoma, and angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: heterogeneity of intrafollicular T-cells and their altered distribution in the pathogenesis of angioimmunoblastic T-cell lymphoma. Hum Pathol. 1999;30(4):403–11.PubMedCrossRefGoogle Scholar
  37. 37.
    Dezube BJ, Aboulafia DM, Pantanowitz L. Plasma cell disorders in HIV-infected patients: from benign gammopathy to multiple myeloma. AIDS Read. 2004;14(7):372–4. 7–9.PubMedGoogle Scholar
  38. 38.
    O’Murchadha MT, Wolf BC, Neiman RS. The histologic features of hyperplastic lymphadenopathy in AIDS-related complex are nonspecific. Am J Surg Pathol. 1987;11(2):94–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Zhang Y, Meyer-Hermann M, George LA, Figge MT, Khan M, Goodall M, et al. Germinal center B cells govern their own fate via antibody feedback. J Exp Med. 2013;210(3):457–64.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Mouillot G, Carmagnat M, Gerard L, Garnier JL, Fieschi C, Vince N, et al. B-cell and T-cell phenotypes in CVID patients correlate with the clinical phenotype of the disease. J Clin Immunol. 2010;30(5):746–55.PubMedCrossRefGoogle Scholar
  41. 41.
    Rakhmanov M, Keller B, Gutenberger S, Foerster C, Hoenig M, Driessen G, et al. Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells. Proc Natl Acad Sci U S A. 2009;106(32):13451–6.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Boursiquot JN, Gerard L, Malphettes M, Fieschi C, Galicier L, Boutboul D, et al. Granulomatous disease in CVID: retrospective analysis of clinical characteristics and treatment efficacy in a cohort of 59 patients. J Clin Immunol. 2013;33(1):84–95.PubMedCrossRefGoogle Scholar
  43. 43.
    Al Kindi M, Mundy J, Sullivan T, Smith W, Kette F, Smith A, et al. Utility of peripheral blood B cell subsets analysis in common variable immunodeficiency. Clin Exp Immunol. 2012;167(2):275–81.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Asano S. Granulomatous lymphadenitis. J Clin Exp Hematopathology : JCEH. 2012;52(1):1–16.CrossRefGoogle Scholar
  45. 45.
    Kuntz M, Goldacker S, Blum HE, Pircher H, Stampf S, Peter HH, et al. Analysis of bulk and virus-specific CD8+ T cells reveals advanced differentiation of CD8+ T cells in patients with common variable immunodeficiency. Clin Immunol. 2011;141(2):177–86.PubMedCrossRefGoogle Scholar
  46. 46.
    Kim HJ, Verbinnen B, Tang X, Lu L, Cantor H. Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature. 2010;467(7313):328–32.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Quigley MF, Gonzalez VD, Granath A, Andersson J, Sandberg JK. CXCR5+ CCR7–CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles. Eur J Immunol. 2007;37(12):3352–62.PubMedCrossRefGoogle Scholar
  48. 48.
    Racz P, Tenner-Racz K, van Vloten F, Schmidt H, Dietrich M, Gluckman JC, et al. Lymphatic tissue changes in AIDS and other retrovirus infections: tools and insights. Lymphology. 1990;23(2):85–91.PubMedGoogle Scholar
  49. 49.
    Keller AR, Hochholzer L, Castleman B. Hyaline-vascular and plasma-cell types of giant lymph node hyperplasia of the mediastinum and other locations. Cancer. 1972;29(3):670–83.PubMedCrossRefGoogle Scholar
  50. 50.
    Schulte KM, Talat N. Castleman’s disease–a two compartment model of HHV8 infection. Nat Rev Clin Oncol. 2010;7(9):533–43.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Susanne Unger
    • 1
  • Maximilian Seidl
    • 1
    • 2
  • Annette Schmitt-Graeff
    • 2
  • Joachim Böhm
    • 3
  • Klaudia Schrenk
    • 1
    • 2
  • Claudia Wehr
    • 1
  • Sigune Goldacker
    • 1
  • Ruth Dräger
    • 1
  • Barbara C. Gärtner
    • 4
  • Paul Fisch
    • 2
  • Martin Werner
    • 2
  • Klaus Warnatz
    • 1
  1. 1.Center for Chronic ImmunodeficiencyUniversity Medical Center Freiburg and University of FreiburgFreiburgGermany
  2. 2.Institute of PathologyUniversity Medical Center FreiburgFreiburgGermany
  3. 3.Institute of PathologyUniversity Hospital AachenAachenGermany
  4. 4.Institute of Medical Microbiology and HygieneSaarland UniversityHomburgGermany

Personalised recommendations