Dr Bergman and colleagues have recently described a case of refractory autoimmune neutropenia (AINP) in a patient carrying the p.A181E (NM_012452) variant of the TACI gene.¹

The patient had a very severe clinical manifestation, including AINP refractory to granulocyte colony-stimulating factor (G-CSF), which was complicated by pure red cell aplasia (PRCA). The authors have highlighted the rarity of the association between an apparent acquired disorder (AINP) and an inherited condition of immune dysregulation.¹

The transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), a member of the tumor necrosis factor receptor superfamily (TNF(R)SF), promotes T-cell-independent antibody responses and plasma cell differentiation and counteracts BAFF-driven B cells. Defects in TNF(R)SF members were first described in common variable immune deficiency and selective immunoglobulin A deficiency, but the spectrum of disorders attributed to TNF(R)SF has widened, involving benign lymphoproliferation and an increased autoimmunity rate.² Abnormal TACI signaling is frequently related to autoimmune “signature,” as shown by the tendency to develop autoimmune cytopenia, which is 3.34-fold higher in patients with TACI mutation than that in the healthy population.^{2, 3}

Increasing evidence suggests that some autoimmune disorders, including cytopenia, represent an early sign of primary immune dysregulation disorders (PIRD). In pediatric patients, a subgroup of inborn errors of immunity, recently named PIRD, has been shown to play a relevant role in the development of autoimmune cytopenia, which is characterized by abnormal functioning of the immune system without severe immunodeficiency, lymphoproliferation, autoimmune disorders, and predisposition to malignancies.^{4, 5} In the case of an attenuated clinical phenotype, these disorders may be easily underestimated, particularly in adults.⁶

However, in pediatric patients, AINP or other mono-/multi-lineage autoimmune cytopenias appear to be epiphenomena of immunedysregulation.⁷ For example, cytopenia can be caused by impaired marrow cell production, as observed in aplastic anemia (AA) and PRCA, or increased destruction of peripheral blood cells, as seen in Evans' syndrome.^{8, 9}

The case reported by Bergman gives us an opportunity to share the experience of the Pediatric Hematology Unit of the IRCCS, G. Gaslini Research Hospital on autoimmune/idiopathic neutropenia, which was initially considered an acquired disorder but was eventually shown to be an immune dysregulation associated with TACI variants.

From 2012 to 2022, 58 patients affected by chronic AINP underwent complete workup, including a dedicated genetic panel. Four of them (one female) were found to have mutated TACI variants. The median age at first observation was 109 months (range, 108–144 months). All patients were in good clinical condition after a follow-up of 30 months (range, 20–90 months) and are currently being followed up at a median age of 174 months (range, 156–324 months). Data were collected according to the Italian Neutropenia Registry (INR) rules approved by the local ethics committee.

Three of four patients had “classical” AINP with positivity for indirect anti-neutrophil antibody. Patient 2 tested negative on the indirect anti-neutrophil antibody test using two consecutive samples. Therefore, according to the INR definition, the patient was considered to have “idiopathic neutropenia.” Given the low sensitivity of the method used (indirect antibodies tests by GIFT), Patient 2 could have been diagnosed with classical AINP on repeat testing.¹⁰

All patients presented with mild or moderate clinical phenotypes. In Patient 2, osteomyelitis in the absence of immunoglobulin depletion or other immunodeficiency features was the reason for the first hospital admission. Patients 3 and 4 had a history of mild recurrence of upper respiratory tract infections and diarrhea during early infancy (Table 1).

Neutropenia was mild in all patients, except in Patient 1, who had severe neutropenia (0.44 × 10³/μl). Leukopenia was present in all patients since the beginning of their clinical history (median white blood cell count: 3.17 × 10³/μl, range, 1.84–3.83 × 10³/μl) and was associated with borderline low lymphocyte count in Patient 1. No association with thrombocytopenia or hemolytic anemia was observed over time.

G-CSF and other immunosuppressants were never administered. No association with other signs or biomarkers of autoimmunity or subsequent appearance of other cytopenias has been observed in this cohort to date.

The immunological pattern of our cohort did not show the expected exhaustion of immunoglobulins; however, lower levels of absolute B cell count were observed in two of four patients. In the three patients in whom B cell subpopulations were studied, the number of marginal zone cells (CD27⁺IgD⁺IgM⁺) was increased compared to reference values, while the number of switched memory cells (CD27⁺IgD⁻IgM⁻) and memory B cells were below the normal range. The number of double-negative (DN) B cells (CD27⁻IgD⁻) was increased compared to normal values in two of three patients.

The number of CD4⁺ and CD8⁺ T cells was normal, whereas that of T regs (CD3⁺CD4⁺ CD25^bright+) was reduced in three of four patients (Table 1).

In patients who underwent bone marrow, maturation was normal with no block at the promyelocyte stage. Cytogenetic abnormalities were not observed.

Genetic analysis using an NGS panel including 161 genes involved in immunodeficiency/immunedysregulations, autoimmune disorders, and marrow failures showed that Patients 1, 2, and 3 had heterozygous pathogenic variants (p.Cys193Ter, p.Ile87Asn, and p.Trp40 Arg, respectively), previously described as risk-increasing TNFRSF13B variants in antibody deficiency syndromes,³ while Patient 4 had the same variant p.Ala181Glu as that reported in Bergman et al.'s case (Table 1).

Overall, our cohort presented with isolated neutropenia with no additional autoimmune markers, mild-to-moderate infection profile (the right ischial branch osteomyelitis of Patient 2 resolved completely after the standard long-term prolonged antibiotic treatment with no recurrence), no substantial limitations of the quality of life, lack of immunoglobulin exhaustion typical of TACI disease but consistent with the young age of the cohort, tendency to have fewer B cells, abnormal switched B cells, and memory B cell depletion, as reported in patients with TACI mutations.^{1, 2}

Pathogenic variants of TACI have incomplete penetrance and variable expression. The presence of a homozygous or heterozygous variant, the possible role of additional genetic variants, or exposure to environmental factors (i.e., microbial exposure) could be responsible for this heterogeneity^{1, 2} and the wide spectrum of clinical features ranging from severe to silent/mild phenotypes.^{1, 2}

It is important to highlight the presentation of TACI disorders with mild symptomatic neutropenia that may further evolve in the long term to severe/refractory mono-/multi-lineage cytopenia, as shown by the case report by Bergman et al.¹ Even if the patient reported by Dr Bergman et al.¹ in good clinical condition up to adulthood, he might have carried some asymptomatic immunological disturbance long before his first admission, consistent with the long time required for the progressive exhaustion of cellular reserves, typical of the natural history of TACI disease.

Differentiating TACI-related neutropenia from a typical primary autoimmune dysfunction may be challenging in infancy.¹⁰ Factors such as older age of presentation, longer duration of neutropenia, leukopenia, and lymphopenia could be signs, as we already described, of “atypical” AINPs.⁷ Moreover, a reduced number of total B cells, B switched cells, and B memory cells with an increase in the number of DN B cells should raise the suspicion of an underlying immune dysregulation.

In particular, an increase in DN B cells has been described in several autoimmune disorders (such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, neuromyelitis optica, myasthenia gravis, and Guillain–Barré syndrome); however, their role in these diseases is unclear. One hypothesis (also seen in a vaccination response model) is that DN B cells may represent a source of disease-relevant immunoglobulins.¹¹

These four cases together with the one described by Bergman et al. highlight that autoimmune cytopenias that show nontypical features or those that are refractory to common therapies require special immunologic and genetic investigation. In our patients, the identification of pathogenic mutations in TACI, one of the most common drivers of PIRD (but not the unique) suggests that the mechanism of neutropenia is likely sustained by dysregulation of the central B cell tolerance with missing self-antigen recognition. In these particular cases tailored follow-up including strict monitoring of immunoglobulin levels/lymphocyte subsets to document any immune cell exhaustion and the clinical surveillance for the appearance of autoimmune signs/surrogate markers is highly recommended.

Early recognition of the type of AINP is critical to offer the best monitoring program and optimal therapy possibly tailored to the underlying disorder (i.e., immunoglobulin replacement), particularly in light of severe clinical findings such as PRCA, which may appear over the course of the disease. This specific type of evolution, as indicated by recent findings from our group,^{8, 9} outlines the need to investigate the underlying PID/PIRD in childhood marrow failure.

Finally, the occurrence of PID/PIRD-related neutropenia in late childhood/young adulthood highlights the importance of establishing good collaborations between pediatricians and hematologists to share diagnostic algorithms and treatment protocols.

Bergman 博士及其同事最近描述了一例携带TACI基因 p.A181E (NM_012452) 变体的患者的难治性自身免疫性中性粒细胞减少症 (AINP)。^1个

该患者临床表现非常严重，包括粒细胞集落刺激因子（G-CSF）难治性 AINP，并并发纯红细胞再生障碍（PRCA）。作者强调了表观获得性疾病 (AINP) 与免疫失调的遗传性疾病之间关联的罕见性。^1个

跨膜激活剂和钙调节剂以及亲环蛋白配体相互作用因子 (TACI)，肿瘤坏死因子受体超家族 (TNF(R)SF) 的成员，促进 T 细胞非依赖性抗体反应和浆细胞分化，并抵消 BAFF 驱动的 B细胞。TNF(R)SF 成员的缺陷首先在常见的可变免疫缺陷和选择性免疫球蛋白 A 缺陷中被描述，但归因于 TNF(R)SF 的疾病范围已经扩大，涉及良性淋巴组织增生和自身免疫率增加。²异常的 TACI 信号通常与自身免疫性“特征”相关，如发生自身免疫性血细胞减少症的趋势所示，TACI 突变患者比健康人群高 3.34 倍。^{2, 3}

越来越多的证据表明，一些自身免疫性疾病，包括血细胞减少，是原发性免疫失调疾病 (PIRD) 的早期征兆。在儿科患者中，最近被命名为 PIRD 的先天性免疫缺陷亚群已被证明在自身免疫性血细胞减少症的发展中发挥了相关作用，其特征是免疫系统功能异常，但没有严重的免疫缺陷、淋巴组织增生、自身免疫性疾病、和恶性肿瘤的倾向。^{4, 5}在临床表型减弱的情况下，这些疾病可能很容易被低估，尤其是在成人中。^6个

然而，在儿科患者中，AINP 或其他单/多谱系自身免疫性血细胞减少似乎是免疫失调的附带现象。⁷例如，在再生障碍性贫血 (AA) 和 PRCA 中观察到的骨髓细胞生成受损可能导致血细胞减少，或者在埃文斯综合征中观察到外周血细胞破坏增加。^{8, 9}

Bergman 报告的病例让我们有机会分享 IRCCS 儿科血液科 G. Gaslini 研究医院关于自身免疫性/特发性中性粒细胞减少症的经验，该病症最初被认为是一种获得性疾病，但最终被证明是一种免疫失调相关疾病与 TACI 变体。

从 2012 年到 2022 年，58 名受慢性 AINP 影响的患者接受了完整的检查，包括专门的基因组。其中四人（一名女性）被发现具有突变的 TACI 变体。首次观察的中位年龄为 109 个月（范围 108-144 个月）。所有患者在随访 30 个月（范围 20-90 个月）后均处于良好的临床状况，目前正在接受随访，中位年龄为 174 个月（范围 156-324 个月）。数据是根据当地伦理委员会批准的意大利中性粒细胞减少症登记处 (INR) 规则收集的。

四名患者中的三名具有“经典”AINP，间接抗中性粒细胞抗体呈阳性。患者 2 使用两个连续样本进行的间接抗中性粒细胞抗体检测呈阴性。因此，根据INR定义，该患者被认为患有“特发性中性粒细胞减少症”。鉴于所用方法的低灵敏度（通过 GIFT 进行的间接抗体测试），患者 2 可能在重复测试时被诊断为经典 AINP。¹⁰

所有患者均表现出轻度或中度临床表型。在患者 2 中，没有免疫球蛋白耗竭或其他免疫缺陷特征的骨髓炎是首次入院的原因。患者 3 和 4 在婴儿早期有上呼吸道感染和腹泻轻度复发史（表 1）。

所有患者的中性粒细胞减少症均为轻度，但患者 1 除外，其患有严重的中性粒细胞减少症 (0.44 × 10 ³ /μl)。自临床病史开始以来，所有患者均出现白细胞减少症（中位白细胞计数：3.17 × 10 3 ^/ μl，范围为 1.84–3.83 × 10 ³ /μl），并且与患者 1 的临界低淋巴细胞计数相关。随着时间的推移，未观察到与血小板减少症或溶血性贫血的关联。

从未使用过 G-CSF 和其他免疫抑制剂。迄今为止，在该队列中未观察到与自身免疫的其他体征或生物标志物或随后出现的其他血细胞减少症相关。

我们队列的免疫学模式没有显示预期的免疫球蛋白耗尽；然而，在四名患者中的两名中观察到较低水平的绝对 B 细胞计数。^{在研究 B 细胞亚群的三名患者中，边缘区细胞 (CD27 +} IgD ⁺ IgM ⁺ )的数量与参考值相比有所增加，而转换记忆细胞 (CD27 ⁺ IgD ⁻ IgM ⁻ ) 和记忆细胞的数量B 细胞低于正常范围。与三名患者中的两名患者的正常值相比，双阴性 (DN) B 细胞 (CD27 ⁻ IgD ⁻ )的数量有所增加。

^{CD4 +}和 CD8 ⁺ T 细胞的数量是正常的，而 T regs (CD3 ⁺ CD4 ⁺ CD25 ^bright+ ) 的数量在四分之三的患者中减少（表 1）。

在接受骨髓移植的患者中，成熟是正常的，早幼粒细胞阶段没有阻塞。未观察到细胞遗传学异常。

使用包括 161 个涉及免疫缺陷/免疫失调、自身免疫性疾病和骨髓衰竭的基因的 NGS 面板进行遗传分析表明，患者 1、2 和 3 具有杂合致病变异（分别为 p.Cys193Ter、p.Ile87Asn 和 p.Trp40 Arg） )，之前被描述为抗体缺陷综合征中风险增加的TNFRSF13B变体， ³而患者 4 具有与 Bergman 等人的病例中报道的相同的变体 p.Ala181Glu（表 1）。

总体而言，我们的队列表现为孤立的中性粒细胞减少症，没有额外的自身免疫标志物，轻度至中度感染特征（患者 2 的右坐骨分支骨髓炎在标准的长期长期抗生素治疗后完全消退，没有复发），没有实质性限制生活质量、缺乏 TACI 疾病典型的免疫球蛋白耗竭但与队列的年轻化一致、B 细胞较少的趋势、异常转换的 B 细胞和记忆 B 细胞耗竭，如 TACI 突变患者所报告的那样。^{1, 2}

TACI 的致病变异具有不完全外显率和可变表达。纯合或杂合变异的存在、其他遗传变异的可能作用或暴露于环境因素（即微生物暴露）可能是造成这种异质性^{1, 2}以及从严重到无症状 /温和的表型。^{1, 2}

重要的是要强调具有轻度症状性中性粒细胞减少症的 TACI 疾病的表现，这些症状可能会在长期内进一步发展为严重/难治性单/多谱系血细胞减少症，如 Bergman 等人的病例报告所示。¹即使 Bergman 博士等人报告的患者。¹直到成年之前，他的临床状况都很好，他可能在第一次入院前很久就携带了一些无症状的免疫障碍，这与细胞储备进行性耗尽所需的长时间一致，这是 TACI 疾病自然病程的典型特征。

在婴儿期将 TACI 相关的中性粒细胞减少症与典型的原发性自身免疫功能障碍区分开来可能具有挑战性。¹⁰年龄较大、中性粒细胞减少、白细胞减少和淋巴细胞减少持续时间较长等因素可能是“非典型”AINP 的征兆，正如我们已经描述的那样。⁷此外，总 B 细胞、B 转换细胞和 B 记忆细胞数量减少以及 DN B 细胞数量增加应引起对潜在免疫失调的怀疑。

特别是，DN B 细胞的增加已在多种自身免疫性疾病（如系统性红斑狼疮、类风湿性关节炎、多发性硬化症、视神经脊髓炎、重症肌无力和格林-巴利综合征）中得到描述；然而，它们在这些疾病中的作用尚不清楚。一个假设（也见于疫苗接种反应模型）是 DN B 细胞可能代表疾病相关免疫球蛋白的来源。¹¹

这四个案例连同 Bergman 等人描述的案例。强调显示非典型特征的自身免疫性血细胞减少症或对普通疗法难以治疗的自身免疫性血细胞减少症需要特殊的免疫学和遗传学调查。在我们的患者中，对 TACI（PIRD 最常见的驱动因素之一（但不是唯一的））致病性突变的鉴定表明，中性粒细胞减少的机制可能是由于中枢 B 细胞耐受性失调和自身抗原识别缺失所致。在这些特殊情况下，强烈建议进行量身定制的后续行动，包括严格监测免疫球蛋白水平/淋巴细胞亚群以记录任何免疫细胞耗竭和自身免疫体征/替代标记物出现的临床监测。

及早识别 AINP 的类型对于提供可能适合潜在疾病（即免疫球蛋白替代）的最佳监测计划和最佳治疗至关重要，特别是考虑到严重的临床表现，例如 PRCA，它可能在治疗过程中出现疾病。^{正如我们小组8、9}最近的发现所表明的，这种特定类型的进化概述了调查儿童骨髓衰竭中潜在的 PID/PIRD 的必要性。

最后，PID/PIRD 相关中性粒细胞减少症在儿童后期/成年早期的发生凸显了在儿科医生和血液学家之间建立良好合作以共享诊断算法和治疗方案的重要性。