TY - JOUR
T1 - Perigranuloma localization and abnormal maturation of B cells emerging key players in sarcoidosis?
AU - Kamphuis, Lieke S.
AU - Van Zelm, Menno C.
AU - Lam, King H.
AU - Rimmelzwaan, Guus F.
AU - Baarsma, G. Seerp
AU - Dik, Willem A.
AU - Thio, H. Bing
AU - Van Daele, Paul L.
AU - Van Velthoven, Mirjam E.
AU - Batstra, Manou R.
AU - Van Hagen, P. Martin
AU - Van Laar, Jan A.
PY - 2013/2/15
Y1 - 2013/2/15
N2 - Rationale: Recent observations of abnormal immunoglobulin responses and case reports describing successful B-cell ablative therapy suggest involvement ofBcells in the pathogenesis of sarcoidosis. Objectives: To investigate how abnormal B-cell maturation and function in patients with sarcoidosis contribute to disease. Methods: Patients with sarcoidosis (n = 32) were included for detailed analysis by immunohistochemistry of tissue, flow cytometry of blood B-cell subsets, andserumimmunoglobulin levels.Vaccinationresponses in patients with sarcoidosis to influenza virus and encapsulated bacteria andmolecular analysis ofimmunoglobulin heavy chain transcriptswere studied for functional analysis of immunoglobulin responses. Measurements and Main Results: Perigranuloma localization of IgAproducing plasma cells and numerous B cells were found in affected tissues. Total blood B-cell numbers were normal, CD271 memory B cells were significantly reduced, and CD272IgA1 B cells were significantly increased; the results are normalized in patients treated with TNF-ablockers.Despitethis,patientshadnormal serumimmunoglobulin levels and normal antigen-specific immunoglobulin responses. IgAand IgGtranscripts, however, showed highfrequencies of somatic hypermutations and increased usage of downstream IgG subclasses, suggestive for prolonged or repetitive responses. Conclusions: The large B-cell infiltrates in granulomatous tissue and increased molecular signs of antibody maturation are indicative of direct involvement of B cells in local inflammatory processes in patients with sarcoidosis. Moreover, CD272IgA1 B cells could be a marker for treatment with TNF-a blockers. These findings of B cells as emerging key players provide a rationale for a systematic study on B-cell ablative therapy in patients with sarcoidosis.
AB - Rationale: Recent observations of abnormal immunoglobulin responses and case reports describing successful B-cell ablative therapy suggest involvement ofBcells in the pathogenesis of sarcoidosis. Objectives: To investigate how abnormal B-cell maturation and function in patients with sarcoidosis contribute to disease. Methods: Patients with sarcoidosis (n = 32) were included for detailed analysis by immunohistochemistry of tissue, flow cytometry of blood B-cell subsets, andserumimmunoglobulin levels.Vaccinationresponses in patients with sarcoidosis to influenza virus and encapsulated bacteria andmolecular analysis ofimmunoglobulin heavy chain transcriptswere studied for functional analysis of immunoglobulin responses. Measurements and Main Results: Perigranuloma localization of IgAproducing plasma cells and numerous B cells were found in affected tissues. Total blood B-cell numbers were normal, CD271 memory B cells were significantly reduced, and CD272IgA1 B cells were significantly increased; the results are normalized in patients treated with TNF-ablockers.Despitethis,patientshadnormal serumimmunoglobulin levels and normal antigen-specific immunoglobulin responses. IgAand IgGtranscripts, however, showed highfrequencies of somatic hypermutations and increased usage of downstream IgG subclasses, suggestive for prolonged or repetitive responses. Conclusions: The large B-cell infiltrates in granulomatous tissue and increased molecular signs of antibody maturation are indicative of direct involvement of B cells in local inflammatory processes in patients with sarcoidosis. Moreover, CD272IgA1 B cells could be a marker for treatment with TNF-a blockers. These findings of B cells as emerging key players provide a rationale for a systematic study on B-cell ablative therapy in patients with sarcoidosis.
KW - Immunoglobulin
KW - Somatic hypermutation
KW - TNF-a
KW - Vaccination response
UR - http://www.scopus.com/inward/record.url?scp=84873960799&partnerID=8YFLogxK
U2 - 10.1164/rccm.201206-1024OC
DO - 10.1164/rccm.201206-1024OC
M3 - Article
C2 - 23239158
AN - SCOPUS:84873960799
SN - 1073-449X
VL - 187
SP - 406
EP - 416
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 4
ER -