Intact B-Cell Signaling and Function With Host B-Cells 47 Years After Transplantation for X-SCID

Abstract

Introduction: Severe Combined Immunodeficiency (SCID) is a life-threatening immunodeficiency caused by several pathogenic genetic variants, and it is characterized by profound defects in T-cell numbers and immune function. First performed in the late 1960's, hematopoietic stem cell transplantation remains the standard treatment for most cases of SCID. There is a growing number of post-transplant SCID patients, and it is imperative to assess the long-term outcomes of these patients. We have reported here the longest follow-up of a post-transplant SCID patient who, to our knowledge, bears the first gamma chain (γc) variant to show intact IL-21 signaling. Case Presentation: The patient presented at 5 months of age with recurrent thrush and Pneumocystis jiroveci pneumonia. In 1971, at the age of 11 months, he received an unconditioned, matched, related donor transplant comprising whole, unprocessed bone marrow. He is now 48 years old without significant illness and has never required immunoglobulin replacement. He exhibits T-dependent vaccine responses. He does suffer from chronic warts and bacterial infections that have worsened in recent years. We confirmed a known pathogenic variant in the IL2RG gene showing a hemizygous variant NM_000206.2:c.675C>A, resulting in p.Ser225Arg. His chimerism studies revealed donor T cells, host B cells, host myeloid cells, and mixed NK cells. Lymphocyte enumeration revealed normal numbers and distribution of B cells. The host B cells carry the pathogenic variant in IL2RG, but, when stimulated with IL-21, they demonstrated intact, γc-dependent signaling. Conclusions: Even with host B cells, reconstitution with donor T cells can be sufficient to allow over four decades of survival when B-cell function is intact. Our case demonstrates that satisfactory B-cell function can arise as a consequence of both intact IL-21 signaling due to a hypomorphic γc variant, and close HLA matching with the donor to allow for effective T-cell help.

Progressive B Cell Loss in Revertant X-SCID

“…The IL2RG variant p.V152A could be hypomorphic and allow for some signaling through the IL7R. Certainly other variants of IL2RG allow for some cytokine signaling, as we recently showed for a variant that allows for IL-21 signaling [19]. In this model, however, one also needs to assert that the capability of partial IL7R signaling is sufficient to allow for genesis of B cells but not T cells, which we have no evidence for.…”

Trends in the Epidemiology of Pneumocystis Pneumonia in Immunocompromised Patients without HIV Infection

“…In some early studies, primary immunodeficiency constitutes the most frequent underlying diseases associated with PCP in infants [ 164 ]. We provided a comprehensive list of primary immunodeficient diseases associated with PCP ( Table 2 and Table S2 [ 86 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 ,…”

Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease

“…The lack of B-cell functional recovery observed in SCID-X1 patients despite successful T-cell reconstitution is likely due to a failure in the signaling through IL-21 in B-cells (14) and is associated with a reduced donor B-cell engraftment particularly in unconditioned procedures (38,(45)(46)(47)(48). Nevertheless, a recent study reported an ongoing B-cell response with intact host B-cell signaling through IL-21 in a SCID-X1 patient 47 years after the HSCT, although this is most likely due to a hypomorphic gc variant (49).…”