A C5a-Immunoglobulin complex in chronic lymphocytic leukemia patients is associated with decreased complement activity

Regina Michelis; Tamar Tadmor; Masad Barhoum; Mona Shehadeh; Lev Shvidel; Ariel Aviv; Galia Stemer; Najib Dally; Naomi Rahimi-Levene; Mona Yuklea; Andrei Braester

doi:10.1371/journal.pone.0209024

A C5a-Immunoglobulin complex in chronic lymphocytic leukemia patients is associated with decreased complement activity

Regina Michelis, Tamar Tadmor, Masad Barhoum, Mona Shehadeh, Lev Shvidel, Ariel Aviv, Galia Stemer, Najib Dally, Naomi Rahimi-Levene, Mona Yuklea, Andrei Braester

Bar-Ilan University - Azrieli Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world. The therapeutic approach to CLL includes chemotherapeutic regimens and immunotherapy. Complement-mediated cytotoxicity, which is one of the mechanisms activated by the therapeutic monoclonal antibodies, depends on the availability and activity of the complement (C) system. The aim was to study the structure of circulating C components and evaluate the importance of C5 structural integrity for C activity in CLL patients. Blood samples were collected from 40 naïve CLL patients and 15 normal controls (NC). The Western blot analysis showed abnormal C5 pattern in some CLL patients, while patterns of C3 and C4 were similar in all subjects. Levels of the C activation markers sC5b-9 and C5a were quantified before and after activation via the classical (CP) and alternative (AP) pathways. In patients with abnormal C5, basal levels of sC5b-9 and C5a were increased while activities of the CP and of the CP C5-convertase, the immediate C5-upstream complex, were decreased compared to NC and to patients with normal C5. The data indicate a link between CP activation and apparent C5 alterations in CLL. This provides a potential prognostic tool that may personalize therapy by identifying a sub-group of CLL patients who display an abnormal C5 pattern, high basal levels of sC5b-9 and C5a, and impaired CP activity, and are likely to be less responsive to immunotherapy due to compromised CP activity.

Original language	English
Article number	e0209024
Journal	PLoS ONE
Volume	14
Issue number	1
DOIs	https://doi.org/10.1371/journal.pone.0209024
State	Published - Jan 2019

Bibliographical note

Publisher Copyright:
© 2019 Michelis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding

This work was supported by the Dangoor Foundation via the Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel (Grant 292956); The Health Corporation of Galilee Medical Center, Nahariya, Israel.

Funders	Funder number
Bar-Ilan University	292956

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10.1371/journal.pone.0209024

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title = "A C5a-Immunoglobulin complex in chronic lymphocytic leukemia patients is associated with decreased complement activity",

abstract = "Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world. The therapeutic approach to CLL includes chemotherapeutic regimens and immunotherapy. Complement-mediated cytotoxicity, which is one of the mechanisms activated by the therapeutic monoclonal antibodies, depends on the availability and activity of the complement (C) system. The aim was to study the structure of circulating C components and evaluate the importance of C5 structural integrity for C activity in CLL patients. Blood samples were collected from 40 na{\"i}ve CLL patients and 15 normal controls (NC). The Western blot analysis showed abnormal C5 pattern in some CLL patients, while patterns of C3 and C4 were similar in all subjects. Levels of the C activation markers sC5b-9 and C5a were quantified before and after activation via the classical (CP) and alternative (AP) pathways. In patients with abnormal C5, basal levels of sC5b-9 and C5a were increased while activities of the CP and of the CP C5-convertase, the immediate C5-upstream complex, were decreased compared to NC and to patients with normal C5. The data indicate a link between CP activation and apparent C5 alterations in CLL. This provides a potential prognostic tool that may personalize therapy by identifying a sub-group of CLL patients who display an abnormal C5 pattern, high basal levels of sC5b-9 and C5a, and impaired CP activity, and are likely to be less responsive to immunotherapy due to compromised CP activity.",

author = "Regina Michelis and Tamar Tadmor and Masad Barhoum and Mona Shehadeh and Lev Shvidel and Ariel Aviv and Galia Stemer and Najib Dally and Naomi Rahimi-Levene and Mona Yuklea and Andrei Braester",

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AU - Michelis, Regina

AU - Tadmor, Tamar

AU - Barhoum, Masad

AU - Shehadeh, Mona

AU - Shvidel, Lev

AU - Aviv, Ariel

AU - Stemer, Galia

AU - Dally, Najib

AU - Rahimi-Levene, Naomi

AU - Yuklea, Mona

AU - Braester, Andrei

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N2 - Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world. The therapeutic approach to CLL includes chemotherapeutic regimens and immunotherapy. Complement-mediated cytotoxicity, which is one of the mechanisms activated by the therapeutic monoclonal antibodies, depends on the availability and activity of the complement (C) system. The aim was to study the structure of circulating C components and evaluate the importance of C5 structural integrity for C activity in CLL patients. Blood samples were collected from 40 naïve CLL patients and 15 normal controls (NC). The Western blot analysis showed abnormal C5 pattern in some CLL patients, while patterns of C3 and C4 were similar in all subjects. Levels of the C activation markers sC5b-9 and C5a were quantified before and after activation via the classical (CP) and alternative (AP) pathways. In patients with abnormal C5, basal levels of sC5b-9 and C5a were increased while activities of the CP and of the CP C5-convertase, the immediate C5-upstream complex, were decreased compared to NC and to patients with normal C5. The data indicate a link between CP activation and apparent C5 alterations in CLL. This provides a potential prognostic tool that may personalize therapy by identifying a sub-group of CLL patients who display an abnormal C5 pattern, high basal levels of sC5b-9 and C5a, and impaired CP activity, and are likely to be less responsive to immunotherapy due to compromised CP activity.

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A C5a-Immunoglobulin complex in chronic lymphocytic leukemia patients is associated with decreased complement activity

Abstract

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Funding

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