What if some of the immune activity we’re looking for isn’t showing up where we expect to find it? In this episode, I sit down with Robyn Puglia of Cyrex Laboratories to explore TG6, lymphocyte patterns, and early autoimmunity —and specialized testing many practitioners may not realize is available through Cyrex Array 3, the Lymphocyte Map, and Array 5 . We look at neurological manifestations of gluten-related disease, what different immune cell populations may add to the clinical picture, and how autoantibodies can sometimes appear before autoimmune disease is diagnosed. The bigger question: Can seeing more of the immune story help us ask better questions about what may be driving a complex presentation? What You’ll Learn Why gluten reactivity isn’t always a gut story. TG6 has been studied in gluten-related neurological disorders, particularly gluten ataxia. (Hadjivassiliou 2019) We discuss why neurological symptoms may belong in the gluten conversation and what Cyrex Array 3 is designed to investigate beyond conventional celiac markers. (Mearns 2019) What your lymphocyte count may not tell you. T cells, B cells, natural killer cells, and their subsets have different jobs. Robyn explains how the Cyrex Lymphocyte Map looks at these populations and how patterns may help practitioners decide what to investigate next. Why autoimmunity may start before the diagnosis. Disease-associated autoantibodies can precede clinical disease in several autoimmune conditions. (Ma 2017) We explore Cyrex Array 5 , tissue-associated autoantibodies, and what these earlier immune signals may—and may not—tell us. (Frazzei 2022) Meet Robyn Puglia Robyn Puglia’s work with celiac disease, neurological symptoms, autoimmunity, and complex chronic illness pushed her to ask what the immune system might be telling us beyond a routine workup. Today, as Vice President of Practitioner Education at Cyrex Laboratories , she teaches practitioners how to think about specialized immune testing without treating an abnormal biomarker as a diagnosis. FAQ What is TG6, and why does it matter? Most practitioners know tissue transglutaminase 2 (TG2) from celiac testing. Tissue transglutaminase 6 (TG6) has been studied in gluten-related neurological disorders, particularly gluten ataxia. (Hadjivassiliou 2019) TG6 isn’t part of routine guideline-supported celiac screening, but it highlights an important point: gluten-related immune disease can have extraintestinal manifestations, including neurological symptoms. (Mearns 2019) (Rubio-Tapia 2023) What is Cyrex Array 3? Array 3 evaluates antibody reactivity to multiple wheat-associated antigens and transglutaminases, including TG6. It provides a broader look at wheat-associated immune reactivity than conventional celiac serology. It shouldn’t replace established evaluation for celiac disease or wheat allergy; the value of additional biomarkers depends on the clinical question and the evidence supporting their intended use. (Rubio-Tapia 2023) (Leonard 2017) What can the Lymphocyte Map show? The Cyrex Lymphocyte Map examines populations and subsets of T cells, B cells, and natural killer cells. Instead of asking whether one value is simply high or low, Robyn looks at the pattern and asks what might explain it. Infection? Medication effects? Immune dysfunction? Another clinical process? The pattern isn’t the diagnosis. It helps sharpen the investigation. Can autoimmunity start before the diagnosis? Yes. In several autoimmune diseases, researchers have detected disease-associated autoantibodies before patients meet formal diagnostic criteria—sometimes years earlier. (Ma 2017) Cyrex Array 5 evaluates multiple tissue-associated autoantibodies that Robyn discusses in this context. But an autoantibody isn’t a crystal ball. Its significance depends on the specific marker, the patient, and the evidence supporting its clinical use. (Ma 2017) Does Cyrex offer all of these tests? Yes. Cyrex offers the specialized tests discussed in this episode, including Array 3, the Lymphocyte Map, and Array 5 , along with additional testing related to mucosal immunity and barrier function. The important question isn’t, “How much can I test?” It’s “What am I trying to understand, and will this result change what I do next?” Timestamps 02:42 — The patients who pulled Robyn deeper into immunology How celiac disease and unexplained illness changed her approach to complex patients. 11:41 — TG6: When gluten becomes a brain conversation Why gluten-related immune activity isn’t necessarily confined to the gut. 13:49 — Are we asking enough questions about wheat? The thinking behind Cyrex Array 3 and its broader look at wheat-associated antigens and transglutaminases. 28:29 — What if autoimmunity starts before the diagnosis? Tissue-associated autoantibodies, Array 5, and preclinical autoimmunity. 33:49 — Your lymphocyte count isn’t the whole story T cells, B cells, natural killer cells, and the Cyrex Lymphocyte Map. 39:25 — The abnormal result is where the investigation starts How immune patterns can generate better clinical questions. 44:20 — Stop looking for one perfect root cause Robyn’s “aggregate gains” approach to complex illness. 50:49 — What else can we see in the immune system? Tissue autoantibodies, mucosal immunity, and barrier biomarkers. 57:42 — When neurological symptoms change the workup Why brain symptoms may require a broader metabolic, vascular, and immune picture. Want to elevate your practice? This episode is sponsored by Fullscript , a comprehensive care delivery platform designed to support whole-person, integrative healthcare. Fullscript allows clinicians to streamline supplement dispensing, lab ordering, and patient education in one free, centralized system—helping reduce administrative burden while supporting clinical decision-making. For practitioners, Fullscript offers access to professional-grade supplements, evidence-informed protocols, and lab integrations that can support more efficient planning and follow-up. For patients, it provides a clear, organized way to receive recommendations, manage refills, and stay engaged in their care. The goal is not to replace clinical judgment, but to make it easier for clinicians to focus on what matters most: thoughtful, individualized patient care. Disclaimer The views expressed on this podcast are those of the hosts and the guests, and they don't necessarily reflect the views of FullScript or any affiliated organizations. This podcast is for informational and educational purposes only, and it's not intended to be medical advice. For your safety, always check with your healthcare provider before making any changes to your healthcare routine. Citations Frazzei, G., van Vollenhoven, R. F., de Jong, B. A., Siegelaar, S. E., & van Schaardenburg, D. (2022). Preclinical autoimmune disease: A comparison of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and type 1 diabetes. Frontiers in Immunology, 13 , 899372. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9281565/ Hadjivassiliou, M., Croall, I. D., Zis, P., Sarrigiannis, P. G., Sanders, D. S., Aeschlimann, P., Grünewald, R. A., Armitage, P. A., Connolly, D., Aeschlimann, D., & Hoggard, N. (2019). Neurologic deficits in patients with newly diagnosed celiac disease are frequent and linked with autoimmunity to transglutaminase 6. Clinical Gastroenterology and Hepatology, 17 (13), 2678–2686. https://www.cghjournal.org/article/S1542-3565(19)30278-2/fulltext Leonard, M. M., Sapone, A., Catassi, C., & Fasano, A. (2017). Celiac disease and nonceliac gluten sensitivity: A review. JAMA, 318 (7), 647–656. https://jamanetwork.com/journals/jama/article-abstract/2648637 Ma, W. T., Chang, C., Gershwin, M. E., & Lian, Z. X. (2017). Development of autoantibodies precedes clinical manifestations of autoimmune diseases: A comprehensive review. Journal of Autoimmunity, 83 , 95–112. https://www.sciencedirect.com/science/article/abs/pii/S0896841117303542 Mearns, E. S., Taylor, A., Thomas Craig, K. J., Puglielli, S., Cichewicz, A. B., Leffler, D. A., Sanders, D. S., Lebwohl, B., & Hadjivassiliou, M. (2019). Neurological manifestations of neuropathy and ataxia in celiac disease: A systematic review. Nutrients, 11 (2), 380. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412791/ Rubio-Tapia, A., Hill, I. D., Semrad, C., Kelly, C. P., Greer, K. B., Limketkai, B. N., & Lebwohl, B. (2023). American College of Gastroenterology guidelines update: Diagnosis and management of celiac disease. The American Journal of Gastroenterology, 118 (1), 59–76. https://pubmed.ncbi.nlm.nih.gov/36602836/