{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:16:29Z","timestamp":1790381789356,"version":"4.1.0"},"reference-count":59,"publisher":"American Society for Clinical Investigation","issue":"10","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":31,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Allergy and Infectious Diseases \/ National Institutes of Health","award":["U19 AI166059"],"award-info":[{"award-number":["U19 AI166059"]}]},{"name":"National Institute of Allergy and Infectious Diseases \/ National Institutes of Health","award":["R21 AI149654"],"award-info":[{"award-number":["R21 AI149654"]}]},{"DOI":"10.13039\/100014576","name":"University of California Office of the President","doi-asserted-by":"crossref","award":["VFR-19-633386"],"award-info":[{"award-number":["VFR-19-633386"]}],"id":[{"id":"10.13039\/100014576","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,22]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>\n                      Disseminated coccidioidomycosis (DCM) is an often fatal and otherwise intractable condition requiring lifelong antifungal treatment. We have previously shown that a deranged polarization of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells toward a Th2 phenotype can exist in the context of DCM. Here, we studied a large population to determine the frequency of abnormal Th2 skewing of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells in patients with coccidioidomycosis and to identify underlying genetic mechanisms supporting this phenotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We collected PBMCs from 204 patients with coccidioidomycosis, including 96 patients with disseminated disease. We measured immune phenotypes and cytokine production by CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells from patients and healthy controls, and comparisons between groups were made based on disease severity and demographics. Whole-genome sequencing was conducted on 180 individuals who also had cytokine profiling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      We found that approximately 25% of patients with DCM had a CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell compartment that was abnormally skewed toward a Th2 phenotype, and Th2 skewing was highly correlated with male sex. Coculture of T cells with the IL-4R\/IL-13R\u2013blocking antibody dupilumab reduced Th2 skewing. Sequencing revealed rare variants in genes involved in the IL-12\/IFN-\u03b3 axis in several Th2-skewed patients, and we validated one such variant in\n                      <jats:italic>IFNGR1<\/jats:italic>\n                      as hypomorphic.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>\n                      Patients with DCM, especially males, should be screened for Th2 skewing of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells. Patients with Th2 skewing should be additionally screened for genetic defects in the IL-12\/IFN-\u03b3 axis. Our findings give a mechanistic rationale for blockade of IL-4R in Th2-skewed patients with refractory coccidioidomycosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>National Institute of Allergy and Infectious Diseases\/NIH grants R21 AI149654 and U19 AI166059 and University of California Office of the President grant VFR-19-633386.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci.insight.199941","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T16:00:58Z","timestamp":1776787258000},"source":"Crossref","is-referenced-by-count":5,"title":["Th2 skewing in patients with disseminated coccidioidomycosis"],"prefix":"10.1172","volume":"11","author":[{"given":"Timothy J.","family":"Thauland","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, 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