CLINICAL RESEARCH ARTICLE

Autoimmune Disease in Islet Transplant Recipients Discontinuing Immunosuppression Late After Lymphodepletion

Alanna Dunn,1 Anna Lam,1,2 Luis Hidalgo,3 A. M. James Shapiro,2,4 and Peter A. Senior1,2 Downloaded from https://academic.oup.com/jcem/article/104/4/1141/5155463 by guest on 26 September 2021 1Division of Endocrinology, University of Alberta, Edmonton, Alberta T6G 2S3, Canada; 2Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta T6G 2C8, Canada; 3Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada; and 4Department of , University of Alberta, Edmonton, Alberta T6G 2B7, Canada

ORCiD numbers: 0000-0001-9064-1984 (A. Dunn).

Context: Clinical islet transplantation (CIT) is an innovative strategy to treat highly selected in- dividuals with type 1 diabetes mellitus (T1DM). Lymphodepletion with alemtuzumab or thymo- globulin is often used for induction therapy in CIT. Alemtuzumab was recently licensed as a treatment of relapsing remitting multiple sclerosis (RRMS). In RRMS, autoimmune (AITD) has developed in up to 40% of individuals treated with alemtuzumab. The appearance of AITD after CIT is not well described. We herein explore factors associated with AITD developing after CIT and any relationship with exposure to lymphodepleting antibodies (alemtuzumab or thymoglobulin).

Case Description: Five cases of AITD developing after CIT for T1DM are described. All were female. Four cases had received alemtuzumab (20 to 40 mg) prior to at least one islet infusion, and one received thymoglobulin induction. The presentation with AITD was 18 to 135 months after first transplant and 11 to 18 months after withdrawal of all maintenance immunosuppression (IS). Four cases presented with clinical and biochemical evidence of from Graves disease. One case presented with biochemical evidence of and positive TSH receptor antibodies. All were treated with conventional therapies for AITD.

Conclusions: Despite routine use of alemtuzumab, clinical presentations of AITD seem to be un- common in patients with CIT receiving IS. However, AITD can develop after withdrawal of IS, highlighting the need for careful thyroid surveillance in this population. (J Clin Endocrinol Metab 104: 1141–1147, 2019)

ype 1 diabetes mellitus (T1DM) is a common disease after CIT may be temporary, protection from hypoglycemia Tresulting from autoimmune destruction of b-cells in is more durable (2). Wider application of CIT in T1DM is pancreatic islets. Although most individuals with T1DM limited by the supply of donor organs but also by the re- are managed effectively with intensive insulin therapy, quirement for chronic immunosuppression (IS). clinical islet transplantation (CIT) has emerged as an at- Lymphodepleting antibodies, including antithymocyte tractive option to restore endogenous, glucose-dependent globulin (thymoglobulin) and alemtuzumab, are used insulin secretion in highly selected people with frequent routinely as induction agents prior to CIT. Mainte- severe hypoglycemia (1). Whereas insulin independence nance IS comprises tacrolimus (PrografTM), combined

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: AITD, autoimmune thyroid disease; CIT, clinical islet transplantation; cPRA, Printed in USA calculated panel-reactive antibody; IS, immunosuppression; RRMS, relapsing remitting Copyright © 2019 Endocrine Society multiple sclerosis; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TPO, Received 1 August 2018. Accepted 30 October 2018. thyroid peroxidase. First Published Online 5 November 2019

doi: 10.1210/jc.2018-01652 J Clin Endocrinol Metab, April 2019, 104(4):1141–1147 https://academic.oup.com/jcem 1141 1142 Dunn et al AITD After Clinical Islet Transplantation J Clin Endocrinol Metab, April 2019, 104(4):1141–1147 with mycophenolate mofetil (cellcept), or sirolimus in Table 1. The indications for CIT included history of (RapamuneTM). glycemic lability, severe episodes of hypoglycemia, hypo- Alemtuzumab (Lemtrada) is a humanized monoclonal glycemia unawareness, and/or diabetic ketoacidosis. All antibody targeting CD52 present on mature lymphocytes, subjects had received two separate islet infusions; one natural killer cells, and monocytes as well as soluble CD52 subject received a third islet infusion. All subjects received (3). It causes rapid lymphodepletion, and the subsequent alemtuzumab, except for case 5, who received thymoglo- pattern of repopulation of immune cells modulates the bulin. Alemtuzumab was administered as a single dose of immune system. This therapy has been used in a variety of 20 mg (case 3) or 30 mg (cases 1, 2, and 4). The lym- clinical scenarios, including treatment of B-cell lymphoma, phodepleting antibodies were administered in combination chronic lymphocytic leukemia (4), allogeneic hematopoietic with etanercept or anakinra or both. Cases 4 and 5 had stem cell transplantation (5), kidney transplantation, and previously received islet infusions without lymphodepleting Downloaded from https://academic.oup.com/jcem/article/104/4/1141/5155463 by guest on 26 September 2021 CIT. More recently, alemtuzumab has been licensed for the antibodies (case 4 received basiliximab 31; case 5 received treatment of relapsing-remitting multiple sclerosis (RRMS) daclizumab and infliximab 32). After transplantation, all (6). In RRMS, alemtuzumab is given by intravenous in- cases were maintained on combinations of tacrolimus fusion (12 mg/d) for 5 consecutive days with a second course (Prograf) with either sirolimus (Rapamune) or mycophe- administered daily for 3 days after 1 year, for a total dose of nolate mofetil (CellCept). Multiagent maintenance IS was 96 mg (7). AITD has emerged as a frequent adverse event withdrawn either because of graft loss, defined as negative in RRMS, developing in 35% to 41% of subjects, most c-peptide levels (,0.02 nmol/L), or intolerable side effects. commonly after some delay (peaking during the third year Cases 4 and 5 were still taking small doses of IS as mon- after first alemtuzumab treatment) (8). otherapy to prevent sensitization to foreign antigens (12) Genetic studies have shown associations between spe- when they were diagnosed with AITD. Their clinical courses cific HLA class 2 alleles and the prevalence of autoimmune are illustrated in Fig. 1. disease, such as T1DM and AITD. Patients with DR4-DQ8 and/or DR17 (3)-DQ2/DQA05 have an increased preva- Case 1 lence of autoimmunity and thus have a higher risk for A 28-year-old woman diagnosed with T1DM at 14 autoimmune disease (9). The association between T1DM years of age received two islet infusions. Sixteen months and AITD is widely recognized in clinical practice (10). Not after the last dose of alemtuzumab and 14 months after surprisingly, 31% of individuals undergoing CIT assess- the withdrawal of all IS, biochemical evidence of hy- ment have a history of AITD (11). Despite routine use perthyroidism was confirmed (Table 2). All previous (roughly two-thirds of patients) of alemtuzumab in subjects thyroid function tests were normal, with no known at high risk for autoimmunity, we have observed very few history of thyroid disease. Her family history is signifi- cases of AITD developing after CIT. We have only observed cant for type 2 diabetes mellitus (T2DM) in her paternal five cases of AITD in CIT recipients occurring after with- grandfather, Crohn disease in a paternal uncle, and drawal of maintenance IS, which prompted us to explore hypertension and colon in other family members. factors that might explain the apparently low rates of AITD She has an identical twin sister with no known auto- relative to those seen in RRMS. immune disease. She reported a 3- to 6-month history of hyperthyroid symptoms, including tachycardia, palpi- Patients and Methods tations, diaphoresis, dizziness, proximal muscle weak- We performed a retrospective chart review of five individuals ness, decreased energy, and weight loss of 8.6 kg. A who had developed AITD after CIT at the University of Alberta. technetium-99m thyroid scan showed diffuse increased Clinical, laboratory, pharmacy, and imaging data were ab- uptake consistent with Graves disease, and she was stracted from the charts. The clinical diagnosis made by the subsequently diagnosed with Graves disease. After initial attending physician was reviewed and corroborated with lab- therapy with methimazole, she received radioiodine oratory and imaging reports. Interventions and response to ablation but required thyroidectomy because of re- treatment were assessed by reviewing operative reports, progress notes, prescription records, and laboratory data. All currence. Currently she is euthyroid on L-thyroxine. subjects gave consent to the chart review and to publication of There have been no complications due to Graves disease. the data, and this study was approved by the Health Research Ethics Board of the University of Alberta (Pro00001120). The Case 2 diagnosis of AITD was confirmed biochemically. A 49-year-old woman who had been diagnosed with Case Series T1DM at 11 years of age and with Addison disease at age 15 received two islet infusions. Twenty-four months after All five subjects are female with longstanding T1DM and the last dose of alemtuzumab and 16 months after no prior history of AITD. Their characteristics are described withdrawal from all IS, she presented with biochemical doi: 10.1210/jc.2018-01652 https://academic.oup.com/jcem 1143

Table 1. Descriptive Summaries of the Cases

Case 1 Case 2 Case 3 Case 4 Case 5 Age 28 49 51 63 53 Gender Female Female Female Female Female BMI 23.8 26.5 22.2 23.1 23.1 Duration of T1DM, y 14 38 39 24 37 HLA DR4-DQ8 DR4-DQ8, DR17 (3)-DQ2/DQA05 DR4-DQ8 DR4-DQ8 DR4-DQ8 Other autoimmune disease None Addison disease RA and SLE None None Family history of autoimmune disease Yes Yes Yes No No Islet equivalents per kg transplanted First transplant 5974 8459 4463 5976 10907 Second transplant 5846 7542 6036 6897 7198 Third transplant —— ——5955 Downloaded from https://academic.oup.com/jcem/article/104/4/1141/5155463 by guest on 26 September 2021 Pretransplant cPRA, % 0 94 0a 00a Posttransplant(s) cPRA, % 98 99 100 0 99 Presence of donor-specific antibodies No No No No No pretransplant Presence of donor-specific antibodies Yes Yes Yes No Yes posttransplant Pretransplant GAD-65 ,3 .25,000 Not done 35.6 Not done Posttransplant GAD-65 Not done Not done ,3 Not done .25,000 Total dose slemtuzumab (mg) or thymoglobulin 60 60 40 30 Thymo, 6 mg/kg Time from first dose lymphodepleting Ab to 18 40 84 62 38 thyroid disease (months) Time from last dose lymphodepleting Ab to 16 24 80 62 38 thyroid disease, mo Time from withdrawal of multiagent maintenance 14 16 12 11 18 immunosuppression to thyroid disease, mo Time from withdrawal of all immunosuppression 14 16 12 N/A 21 to thyroid disease, mo

Abbreviations: cPRA, calculated panel-reactive antibody; GAD-65, glutamic acid decarboxylase 65-kDa isoform; N/A, not applicable; SLE, systemic lupus erythematosus. acPRA values assumed 0% from negative anti-HLA screen. hyperthyroidism (Table 2). None of her previous thyroid biochemistry (Table 2). She had no known personal or function tests was abnormal, and neither she nor her family history of thyroid disease. A paternal aunt had family has a prior history of thyroid disease. Her brother T1DM, and her mother had hypertension and coronary and sister have T1DM, her sister and daughter have disease. Addison disease, and her father had T2DM. Upon pre- sentation, she reported a 7-month history of anxiety, tremor, Case 4 insomnia, and weight loss of 9.0 kg. A technitium-99m A 63-year-old woman diagnosed with T1DM at 39 thyroid scan showed diffuse increased uptake consistent years of age received two islet infusions. The first transplant with Graves disease on a background of multiple nodules. was complicated by a branch portal venous thrombosis and As a result, she was diagnosed with Graves disease and is the second by liver capsular rupture and leukopenia. Sixty- being treated with methimazole. She has had no compli- eight months after her first transplant, 62 months after her cations due to Graves disease. second transplant (with alemtuzumab), and 11 months after withdrawal from multidrug maintenance IS (with continu- Case 3 ation of low-dose CellCept to prevent HLA sensitization), A 51-year-old woman diagnosed with T1DM at she presented with biochemical hypothyroidism and positive 12 years of age and with rheumatoid arthritis and sys- thyroid peroxidase (TPO) antibodies (Table 2). A pre- temic lupus erythematosus at age 20 received two islet sumptive diagnosis of Hashimoto disease was made, and infusions. Eighty months after the last dose of alemtu- was initiated. Nine months later she was noted zumab and 12 months after withdrawal from all IS, she to have positive TSH receptor antibody. She is currently presented with biochemical hyperthyroidism and a his- euthyroid and on levothyroxine. Neither she nor her family tory of tachycardia, weight loss, poor sleep, anxiety, has a prior history of thyroid disease, and the only important ophthalmopathy, and tremor. A diagnosis of Graves family history was a diagnosis of T2DM in her father. disease and Graves ophthalmopathy was made. Her hyperthyroidism has been successfully treated with Case 5 methimazole. Prior to hyperthyroidism, there was a short A 53-year-old woman diagnosed with T1DM at age period when subclinical hypothyroidism was noted on 16 received three islet infusions. She received lymphodepletion 1144 Dunn et al AITD After Clinical Islet Transplantation J Clin Endocrinol Metab, April 2019, 104(4):1141–1147

only with the third infusion (thymoglobulin at cumulative dose of 6 mg/kg, IV). She presented with alopecia areata 8 months after the third transplant due to increased suscep- tibility to autoimmunity, as a side effect of transplantation, or as a medication side effect (13). Ten years after her first transplant and 26 months after her last transplant, she pre- sented with biochemical hypothyroidism and was successfully treated with levothyroxine for a few months. Thirteen months later, she presented with biochemical hyperthyroidism (Table 2) and a history of tremor, heat intolerance, sweating, and palpitations over the prior 2 to 3 months. The presentation of Downloaded from https://academic.oup.com/jcem/article/104/4/1141/5155463 by guest on 26 September 2021 hyperthyroidism was 29 months after the IS was decreased to low-dose monotherapy (mycophenolate) to prevent HLA sensitization, which she remained on for 1 month after bio- chemical hyperthyroidism. She was treated with methimazole for 27 months before antithyroid drugs were withdrawn. She remains in remission from Graves disease. She had no per- sonal or family history of thyroid disease, and the only sig- nificant family history was a diagnosis of T2DM in her paternal uncle.

Discussion

We have described five cases of AITD developing after some interval in CIT recipients. All cases had prior ex- posure to lymphodepleting antibodies, with four re- ceiving cumulative doses of 30 to 60 mg of alemtuzumab and one with 6 mg/kg thymoglobulin. The earliest ap- pearance of AITD was 16 months after the last dose of alemtuzumab or thymoglobulin; the longest interval was 80 months (Table 1). All cases of AITD developed after complete or func- tional (substantial reduction) withdrawal of maintenance IS. Indeed, the temporal relationship with appearance of AITD seemed to be more closely related to withdrawal of IS (11 to 18 months) than exposure to lymphodepletion (16 to 80 months). In cases 1 and 2 the intervals were similar because IS was withdrawn shortly after the most recent infusion (2 and 8 months between the most recent infusion and discontinuation of IS, respectively). Four of the five cases presented with hyperthyroidism (leading to a clinical diagnosis of Graves disease), with one case presenting with hypothyroidism. Although this latter case was initially attributed to Hashimoto disease, the presence of TSH receptor antibodies suggests that this was a case of AITD with blocking antibodies (14, 15). Figure 1. Clinical course of each of the five cases depicting TSH Two cases had significant thyroid eye disease. One levels, time of CIT (Tx), time on multiagent maintenance subject (case 1) had very difficult-to-manage Graves immunosuppression (MIS), single-agent immunosuppression (SIS), disease, with a very rapid and aggressive relapse shortly time with positive C peptide levels (.0.02 nmol/L), time of thyroid disease diagnosis (Dx), time on Tapazole (methimazole) or Synthroid after radioiodine ablation (579 MBq). She ultimately (levothyroxine) therapy, and time of radioiodine therapy (RAI), if required an urgent thyroidectomy due to severe vomiting applicable. The reference range for TSH is 0.4 to 4.2 mU/L and is and near thyroid storm. Anecdotal reports suggest that indicated on the graphs as the region between the dashed lines. Graves developing after alemtuzumab in RRMS may be doi: 10.1210/jc.2018-01652 https://academic.oup.com/jcem 1145

Table 2. Thyroid Function Tests at Time of Diagnosis of Thyroid Disease

TSHa Thyroid Eye Case (mU/L) FT4b (pmol/L) FT3c (pmol/L) anti-TPO TRAbs Thyroid Scan Disease Treatment 1 ,0.01 53.6 8.3 Negative Positive Diffuse uptake No Methimazole, radioactive iodine, and thyroidectomy 2 0.02 21.0 10.0 Negative Positive Diffuse uptake No Methimazole 3 ,0.03 41.3 17.0 Positive Positive Not done Yes Methimazole 4 49.06 Not done Not done Positive Positive Not done No Levothyroxine 5 ,0.03 45.8 Not done Positive Positive Diffuse uptake Yes Methimazole

Abbreviations: anti-TPO, antithyroid peroxidase antibody; FT3, ; FT4, thyroxine; TRAb, TSH receptor antibody. aReference values for TSH are 0.4–4.2 mU/L. Downloaded from https://academic.oup.com/jcem/article/104/4/1141/5155463 by guest on 26 September 2021 bReference values for FT4 are 9.0–23.0 pmol/L. cReference values for FT3 are 3.5–6.5 pmol/L. more aggressive (15). This would appear to hold for case rather low considering their high risk for other auto- 1, and it is worth noting that cases 2 and 3 required long immune diseases and the routine use of alemtuzumab, courses and/or high doses of methimazole. It seemed which is associated with high rates of AITD when used in most easy to achieve sustained remission in case 5, who RRMS. All of our cases were genetically predisposed to had received thymoglobulin. Previous reports have autoimmunity, sharing HLA type DR4-DQ8, and case 2 suggested that AITD developing after alemtuzumab in had both DR4-DQ8 and DR17 (3)-DQ2/DQA05 alleles RRMS may be more likely to be biphasic (15). This was (Table 1). the pattern observed in cases 3 and 5, who had transient It is important to note the potentially key role of hypothyroidism before clinical presentation with hy- maintenance IS to prevent AITD after lymphodepletion. perthyroidism. Because of the risk of biphasic disease, There is a previous report of Graves disease developing case 4 is being monitored carefully for symptoms or among islet transplant recipients who had discontinued IS biochemical evidence of hyperthyroidism. (16). In this previous report, there was an association with The cases described include those with clinical symptoms the presence of TPO antibodies prior to transplant. In of hyperthyroidism and those who were identified with contrast, all our cases had positive TSH receptor antibodies, thyroid disease as part of our routine monitoring (TSH and two cases did not have TPO antibodies when they every 6 months). Three cases of asymptomatic hypothy- presented with hyperthyroidism. This prior report and data roidism (cases 3, 4, and 5) were then monitored more from case 5 in this report suggest that the development of closely, with two cases (cases 3 and 5) developing clinical Graves disease is not peculiar to alemtuzumab but may be symptoms of hyperthyroidism. Mild, transient, or sub- associated with lymphodepletion in general. clinical AITD may have been overlooked among CIT re- Withdrawal of IS was either because of intolerable side cipients, and we are thus unable to estimate the risk of effects while insulin independent (n = 1) or graft dys- AITD after CIT in general among those exposed to function as a result of inadequate exposure to effective IS alemtuzumab or in those who have IS withdrawn. Nev- due to side effects or noncompliance (n = 3) and was ertheless, we have a substantial cohort of islet transplant associated with an increased degree of HLA sensitization recipients who have been exposed to alemtuzumab. Be- [elevated calculated panel-reactive antibody (cPRA)] tween 1999 and 2018, 268 individuals with T1DM re- after withdrawal of IS. We do not know whether donor- ceived islet transplants at our institution. Alemtuzumab was specific antibodies contributed to graft loss in the cases first used in our program in 2002, and to date 180 in- with inadequate IS because these were not measured dividuals have received alemtuzumab with one or more islet prior to graft loss. Previous reports indicate that sensiti- infusions. Whereas almost all CIT recipients with graft zation is uncommon with adequate IS (10). The cause of function and maintained on IS remain under close follow- graft loss without elevation in cPRA in case 4 is not up, we have little or no contact with individuals who have known. We are unable to comment on the potential role of discontinued IS and who may be at higher risk for AITD. A diabetes autoantibodies because we have very limited systematic evaluation of all recipients, which should correct anti–glutamic acid decarboxylase antibody data (Table 1). for previous radioiodine ablation or thyroidectomy in It remains unclear from this limited study whether patients who presumably are notatriskforincidentAITD, these cases of AITD are mediated predominantly by is required to confidently assess the risk of AITD. exposure to lymphodepleting antibodies, withdrawal Among CIT recipients who continue maintenance IS, of maintenance IS, a strong underlying predisposition the number of cases of clinically apparent AITD appears to autoimmunity, or a combination of these factors. 1146 Dunn et al AITD After Clinical Islet Transplantation J Clin Endocrinol Metab, April 2019, 104(4):1141–1147

Autoimmune thyroid disease is likely the result of a present until these cells have adequately regenerated, complex interplay of multiple genetic, hormonal, and fitting with the delay seen in AITD presentation after environmental factors. alemtuzumab (27). Although not directly assessed in our studies, Th1 Immune modulating therapies are increasingly used in lymphocytes play a key role in the pathogenesis of AITD clinical practice, particularly in oncology. Checkpoint in- (17). T cell depletion soon after alemtuzumab treatment hibitors appear to be particularly important causes of a is nonselective for T cell subsets. However, there are range of autoimmune diseases (28). More detailed un- differences in reconstitution rates. Th1 and Th17 subsets, derstanding of the complex interplay between immune cells both linked to various autoimmunities including AITD together with genetic factors, antigen exposure, thymic (17), show an overall decrease after alemtuzumab ad- reserve, homeostatic cytokines, and environmental factors ministration when examined out to 2 years after alem- will be valuable. The relative contributions of induction vs Downloaded from https://academic.oup.com/jcem/article/104/4/1141/5155463 by guest on 26 September 2021 tuzumab (18, 19). The decrease in these proinflammatory maintenance IS will also need detailed exploration. Th subsets is accompanied by an increase in regulatory Although there are reports of thyroid disease after the T cells. In renal transplant recipients, alemtuzumab is use of some immunosuppressive agents, such as anti– associated with an increase in Th17 lymphocytes when CTLA-4 agents and antithymocyte globulin (4, 16), it mycophenolate mofetil is withdrawn, but their pro- seems to be a relatively rare event relative to the expe- liferation and cytokine production are regulated by Tregs rience with alemtuzumab in RRMS. One previous study (20). A role for Th17 lymphocytes in autoimmune dis- in a small cohort of CIT recipients treated with thymo- orders has been suggested (21). Recently, the importance globulin who had withdrawal of IS described five cases of the imbalance of higher Th17 cells to low Treg cells has of AITD developing 2 to 21 months after withdrawal. been implicated to be involved in AITD (22) as well as The authors attribute the development of AITD to the chronic B cell activity and thyroid autoantibody pro- reappearance of pre-existing anti-TPO antibodies, which duction (23). Alemtuzumab causes profound lymphocyte had been suppressed while on IS (16). depletion, and the sequence of repopulation has been A potential explanation for our observations is that postulated to result in the stimulation of autoantibody repopulation of lymphocytes after lymphodepletion is an production and the appearance of autoimmune disease important risk factor for AITD, which may be inhibited by (6). Recovery of B cell counts after lymphodepletion is the presence of maintenance IS, which, although directed to generally complete within 6 to 8 months, compared with the prevention of alloimmunity, may suppress autoreactive recovery of T cell counts within 1 to 3 years (24, 25). cells. Withdrawal of IS may result in unrestrained auto- Furthermore, the pattern of T cell regeneration is im- immunity resulting in clinical manifestations such as AITD. portant, with higher proportions of CD8+ T cells and Treg Our data and previous studies (16) suggest that careful cells relative to other T cell subtypes seen after alemtu- monitoring of thyroid function be performed in islet zumab (26). This sustained increase in Tregs is a suggested transplant recipients exposed to lymphodepleting anti- cause of the long-term efficacy of alemtuzumab in bodies. Special attention (e.g., with TSH monitoring RRMS (24). every 3 to 6 months for 3 years then annually) should be There are two main hypotheses to explain the high risk paid to individuals who have discontinued IS and would of AITD after alemtuzumab for RRMS. First, after normally be discontinued from regular follow-up. profound lymphodepletion, homeostatic proliferation of Future studies should undertake a systematic survey T cells may allow proliferation of pathogenic CD8+ among former CIT recipients who have discontinued IS T cells that have avoided clonal deletion because of the and prospectively monitor for AITD to precisely de- reduced thymic function seen with aging. Although there termine the risk of AITD after CIT. are also increased Treg cells compared with other T cell subsets, the absolute number of these cells has been Acknowledgments suggested to be insufficient to prevent autoantibody production (26). An alternative hypothesis suggests a The authors thank the clinical nurse coordinators and program more prominent role for B cell–mediated, rather than staff for assistance in facilitating the chart review and the patients whose cases are described. T cell–mediated, AITD. Because B cells repopulate rap- Financial Support: A.D. was supported by a Jody Ginsberg idly in the absence of effective T cell regulation, in- Scholarship from the Division of Endocrinology, University of dividuals with a genetic susceptibility for autoimmunity Alberta. may have autoreactive B cells, which evade immune Correspondence and Reprint Requests: Peter A. Senior destruction and proliferate. However, autoantibody MBBS, PhD, Division of Endocrinology, University of Alberta, production is also dependent on CD4+ T cell function. 9.114 CSB, 11350 83 Avenue, Edmonton, Alberta T6G 2S3, According to this hypothesis, autoimmunity does not Canada. E-mail: [email protected]. doi: 10.1210/jc.2018-01652 https://academic.oup.com/jcem 1147

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