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Q52. Abnormalities in the immune system are common and important in chronic lymphocytic leukemia (CLL) leading to the infections, second malignancies, and autoimmune complications. 以下敘述有關於 immune dysfunction in CLL 哪一項是錯誤的?

  • (A) Hypogammaglobulinemia
  • (B) Abnormalities in complement activation
  • (C) Dysfunction in neutrophils
  • (D) T cell abnormalities does not occur
  • (E) Dysfunction in monocytes
點此顯示正解

(D) T cell abnormalities does not occur

詳解

Analysis

The stem asks for the WRONG (incorrect/false) statement about immune dysfunction in CLL.

1) Why (D) is the WRONG statement:

Option (D) states "T cell abnormalities does not occur" — this is definitively false. T cell abnormalities are a well-established hallmark of CLL immune dysfunction13457. Multiple comprehensive reviews document extensive T cell alterations including:

  • Phenotypic abnormalities: Oligoclonal T cell expansions, restrictions in T cell receptor gene repertoire, and shared TCR clonotypes among patients3
  • Functional defects: Impaired proliferation, reduced cytotoxicity, defective immunological synapse formation, and metabolic exhaustion5
  • Exhaustion phenotype: Expression of multiple inhibitory receptors (PD-1, Tim-3, CTLA-4) with features of chronic antigenic stimulation13
  • Subset imbalances: CD4+ T cell depletion, expansion of exhausted CD8+ subsets, increased regulatory T cells (Tregs), and dysregulation of cytokine signaling47

The literature emphasizes that T cell dysfunction is present even in untreated patients, indicating it is intrinsic to CLL pathophysiology13. These T cell abnormalities contribute to impaired anti-tumor immunity, increased viral infections (HSV, CMV, VZV), and poor responses to immunotherapies including CAR T-cell therapy134.

Figure 2: Dysregulations, functional impairments, and phenotypic alterations of immune cells in CLL. The interactions between leukemic cells and immune cells contribute to the establishment of a permissive or even supportive microenvironment that favors tumor progression. APRIL, A proliferation‐inducing ligand; Arg‐1, arginase 1; BAFF, B‐cell activating factor; BCR, B cell receptor; B‐reg, regulatory B cell; CTL, cytotoxic T‐lymphocyte; CLL, chronic lymphocytic leukemia; CTLA‐4, cytotoxic T‐lymphocyte antigen‐4; DC, dendritic cell; Gal‐9, galectin‐9; IDO, indoleamine‐pyrrole 2,3‐dioxygenase; IFN‐γ, interferon‐gamma; IL‐10, interleukin‐10; iNKT, invariant natural killer T cell; iNOS, inducible nitric oxide synthase; MAIT, mucosal‐associated invariant T; MDSC, myeloid‐derived suppressor cell; MHC, major histocompatibility complex; MR1, MHC related protein 1; NET, neutrophil extracellular trap; NK, natural killer cell; NLC, nurse‐like cell; PD‐1, programmed death‐1: PD‐L1, programmed death ligand‐1; PGE2, prostaglandin E2; ROS, reactive oxygen species; TAM, tumor‐associated macrophage; TAN, tumor‐associated neutrophil; T‐reg, regulatory T cell; γδ T‐cell, gamma‐delta T cell; TCR, T cell receptor; Tim‐3, T‐cell immunoglobulin and mucin domain‐3; TGF‐β, Transforming growth factor‐β; TNF‐α, tumor necrosis factor alpha; Th, T helper. Figure created with Inkscape software.

2) Why the other options are TRUE (and therefore not the answer):

(A) Hypogammaglobulinemia — TRUE and well-documented. Hypogammaglobulinemia is a hallmark of CLL, occurring in the majority of patients and associated with worse survival outcomes7[^8]. It results from displacement of normal B lymphocytes by neoplastic cells, defective B-cell maturation due to abnormal T-cell function, and suppression of bone marrow plasma cells[8][9]. This leads to recurrent bacterial infections and poor vaccine responses7[8][10].

(B) Abnormalities in complement activation — TRUE. Complement system abnormalities, particularly classical pathway deficiencies, are well-established in CLL7[9][10][^11]. These defects diminish opsonization and impair clearance of encapsulated bacteria, contributing to increased risk of pneumonia and invasive bacterial infections[^10]. Both quantitative and functional complement deficiencies are documented7.

(C) Dysfunction in neutrophils — TRUE. Neutrophil abnormalities are part of the innate immune defects in CLL7[9][10]. Documented defects include reduced chemotaxis and impaired oxidative burst, leading to poor bacterial clearance and increased susceptibility to fungal infections[^10]. These neutrophil dysfunctions contribute to the overall impaired pathogen defense seen in CLL patients[^9].

(E) Dysfunction in monocytes — TRUE. Monocyte abnormalities are explicitly documented as part of the innate immune dysfunction in CLL7[^9]. The literature describes impaired monocyte function alongside neutrophil defects, contributing to reduced microbial clearance and poor opsonization7. Monocytes can differentiate into nurse-like cells in the CLL microenvironment, which support leukemic cell survival[^9].

Summary: Option (D) is the only false statement. T cell abnormalities are extensively documented and represent a critical component of CLL-associated immune dysfunction, affecting both disease progression and susceptibility to infections.

詳解 · 中文翻譯

分析

題幹要求找出錯誤的（不正確/虛假的）關於 CLL 免疫功能障礙的敘述。

1) 為什麼 (D) 是錯誤的敘述：

選項 (D) 陳述「T 細胞異常不會發生」— 這是絕對虛假的。T 細胞異常是 CLL 免疫功能障礙的公認特徵13457。多項全面的文獻記錄了廣泛的 T 細胞改變，包括：

  • 表型異常：寡克隆 T 細胞擴張、T 細胞受體基因庫存限制，以及患者間的共享 TCR 克隆型3
  • 功能缺陷：增生能力受損、細胞毒性降低、免疫突觸形成缺陷，以及代謝耗盡5
  • 耗盡表型：多種抑制受體（PD-1、Tim-3、CTLA-4）的表達具有慢性抗原刺激特徵13
  • 亞群失衡：CD4+ T 細胞耗盡、耗盡 CD8+ 亞群的擴張、調節性 T 細胞（Tregs）增加，以及細胞因子信號轉導失調47

文獻強調 T 細胞功能障礙即使在未經治療的患者中也存在，表明它對 CLL 病理生理學是內在的13。這些 T 細胞異常導致抗腫瘤免疫力受損、病毒感染增加（HSV、CMV、VZV），以及對包括 CAR T 細胞治療在內的免疫療法反應不佳134。

Figure 2: Dysregulations, functional impairments, and phenotypic alterations of immune cells in CLL. The interactions between leukemic cells and immune cells contribute to the establishment of a permissive or even supportive microenvironment that favors tumor progression. APRIL, A proliferation‐inducing ligand; Arg‐1, arginase 1; BAFF, B‐cell activating factor; BCR, B cell receptor; B‐reg, regulatory B cell; CTL, cytotoxic T‐lymphocyte; CLL, chronic lymphocytic leukemia; CTLA‐4, cytotoxic T‐lymphocyte antigen‐4; DC, dendritic cell; Gal‐9, galectin‐9; IDO, indoleamine‐pyrrole 2,3‐dioxygenase; IFN‐γ, interferon‐gamma; IL‐10, interleukin‐10; iNKT, invariant natural killer T cell; iNOS, inducible nitric oxide synthase; MAIT, mucosal‐associated invariant T; MDSC, myeloid‐derived suppressor cell; MHC, major histocompatibility complex; MR1, MHC related protein 1; NET, neutrophil extracellular trap; NK, natural killer cell; NLC, nurse‐like cell; PD‐1, programmed death‐1: PD‐L1, programmed death ligand‐1; PGE2, prostaglandin E2; ROS, reactive oxygen species; TAM, tumor‐associated macrophage; TAN, tumor‐associated neutrophil; T‐reg, regulatory T cell; γδ T‐cell, gamma‐delta T cell; TCR, T cell receptor; Tim‐3, T‐cell immunoglobulin and mucin domain‐3; TGF‐β, Transforming growth factor‐β; TNF‐α, tumor necrosis factor alpha; Th, T helper. Figure created with Inkscape software.

2) 為什麼其他選項是正確的（因此不是答案）：

(A) 低免疫球蛋白血症 — 正確且文獻充分記載。低免疫球蛋白血症是 CLL 的特徵，發生於大多數患者且與更差的存活結果相關7[^8]。它源於正常 B 淋巴細胞被腫瘤細胞替代、T 細胞功能異常導致的 B 細胞成熟缺陷，以及骨髓漿細胞的抑制[8][9]。這導致反覆性細菌感染和疫苗反應不佳7[8][10]。

(B) 補體激活異常 — 正確。補體系統異常，特別是經典途徑缺陷，在 CLL 中是公認的7[9][10][11]。這些缺陷減少了調理作用並損害了被膜細菌的清除，導致肺炎和侵襲性細菌感染風險增加[10]。定量和功能性補體缺陷均已被記錄7。

(C) 中性粒細胞功能障礙 — 正確。中性粒細胞異常是 CLL 中先天免疫缺陷的一部分7[9][10]。已記載的缺陷包括化學趨向性降低和氧化爆發受損，導致細菌清除不佳和真菌感染易感性增加[^10]。這些中性粒細胞功能障礙導致 CLL 患者整體病原體防禦受損[^9]。

(E) 單核細胞功能障礙 — 正確。單核細胞異常被明確記載為 CLL 先天免疫功能障礙的一部分7[^9]。文獻描述了單核細胞功能受損與中性粒細胞缺陷並行，導致微生物清除減少和調理作用不佳7。單核細胞可在 CLL 微環境中分化為護理樣細胞，支持白血病細胞存活[^9]。

總結：選項 (D) 是唯一虛假的敘述。T 細胞異常已得到廣泛記載，代表 CLL 相關免疫功能障礙的關鍵成分，影響疾病進展和感染易感性。

參考文獻 (AMA)

  1. Roessner PM, Seiffert M. T-Cells in Chronic Lymphocytic Leukemia: Guardians or Drivers of Disease?. Leukemia. 2020;34(8):2012-2024. doi:10.1038/s41375-020-0873-2. PMID:32457353. ↩↩↩↩↩↩↩↩

  2. Vlachonikola E, Stamatopoulos K, Chatzidimitriou A. T Cells in Chronic Lymphocytic Leukemia: A Two-Edged Sword. Frontiers in Immunology. 2020;11:612244. doi:10.3389/fimmu.2020.612244. PMID:33552073. ↩

  3. Martino EA, Caserta S, Vigna E, et al. Infections in Chronic Lymphocytic Leukemia: Evolving Risks and Prevention Strategies. European Journal of Haematology. 2026;116(3):204-214. doi:10.1111/ejh.70065. PMID:41292288. ↩↩↩↩↩↩↩↩↩↩

  4. Lopez-Sanchez C, van Bruggen JAC, Kater AP. Tumor-Associated Disruption of T Cell Receptor Signaling: Lessons Across Cancers With Implications for CLL. Leukemia & Lymphoma. 2025;:1-9. doi:10.1080/10428194.2025.2587786. PMID:41236817. ↩↩↩↩↩↩

  5. Taghiloo S, Asgarian-Omran H. Cross-Talk Between Leukemic and Immune Cells at the Tumor Microenvironment in Chronic Lymphocytic Leukemia: An Update Review. European Journal of Haematology. 2024;113(1):4-15. doi:10.1111/ejh.14224. PMID:38698678. ↩↩↩↩

  6. Otani IM, Lehman HK, Jongco AM, et al. Practical Guidance for the Diagnosis and Management of Secondary Hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees. The Journal of Allergy and Clinical Immunology. 2022;149(5):1525-1560. doi:10.1016/j.jaci.2022.01.025. PMID:35176351. ↩

  7. Vitale C, Boccellato E, Comba L, et al. Impact of Immune Parameters and Immune Dysfunctions on the Prognosis of Patients With Chronic Lymphocytic Leukemia. Cancers. 2021;13(15):3856. doi:10.3390/cancers13153856. PMID:34359757. ↩↩↩↩↩↩↩↩↩↩↩↩↩↩↩↩↩↩

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