~Teachingcenter的醫學筆記~

免疫缺陷疾病(免疫缺乏疾病) Immunodeficiency Disorder

根據發生的原因，可以分為兩大類

Primary immunodeficiency disorders：先天基因遺傳

Secondary immunodeficiency disorders：因其他疾病而造成

在人類的免疫缺失疾病(immunodeficiency disorders)主要有四大類
= 體液性免疫缺損(B細胞或抗體製造的缺陷)
= 細胞性免疫缺損(T細胞/合併T細胞及B細胞)
= 吞噬細胞(phagocytes)、殺手細胞(NK cells)的缺陷
= 補體的缺陷

體液性免疫缺損(B細胞或抗體製造的缺陷)
B細胞發育或功能缺陷導致的immunodeficiency disorders，稱為defects in humoral immunity，使身體對抗extracellular pathogens的能力下降
=較為嚴重的類別(severe)
1. Bruton’s X-linked infantile agammaglobulinemia (XLA)
-----X-linked recessive disorder
-----Tyrosine kinase缺陷(Bruton’s tyrosine kinase)，使B細胞無法成熟
-----出生6個月後開始發生
-----可被許多病原體感染
-----可注射intravenous immunoglobulin (IVIG)治療
2. Common variable immunodeficiency (CVID)
-----多見於青壯年，有反覆細菌感染史
-----血清IgG低，IgA和IgM減少，但血中B細胞數量可能正常
-----患兒及其家族中血清Ig濃度異常，且容易出現自身抗體、自身免疫性疾病或腫瘤
-----CD4⁺ T cells數量↓，CD8⁺T cells數量↑
=相對較輕微的類別(less severe)
1. Selective IgA immunodeficiency
-----血清IgA極低，分泌型IgA缺乏
-----血清IgG、IgM正常；部分IgG2、IgG4缺乏；部分患兒IgM↑
-----可以無症狀，或嬰幼兒期反覆呼吸道、胃腸道、泌尿道感染
-----可出現自體免疫病、過敏疾病、腸吸收不良症候群
-----T cells數量正常，B cells數量正常，但IgA陽性的B cells缺乏
2. IgG subclass immunodeficiencies
-----容易反覆細菌感染
-----在血清IgG1、IgG2、IgG3、IgG4中，有1種或者多種缺乏
-----其中又以IgG3缺乏相對常見
-----低於同年齡兒正常均數2個標準差
-----IgG總數正常或者偏低，除IgG4缺乏可能伴有IgA缺乏外，一般IgA、IgM正常
----- T cells數量正常，B cells數量正常或者不成熟
 

細胞性免疫缺損
T細胞發育或功能缺陷導致的immunodeficiency disorders，稱為disorders of cell-mediated immunity，可能是先天異常，或由病毒、黴菌或原蟲所導致
=後天
HIV感染→AIDS
=先天
1. Severe combined immunodeficiency (SCID) – X-linked (最常見的SCID)
-----X-linked recessive
-----interleukin-2 receptor (IL-2R) gamma chain出現異常
-----有共同結構的IL-4R, IL-7R, IL-11R, IL-15R也會出現異常
-----缺乏T細胞、NK細胞，B細胞數量可能正常但無功能，Ig低下
-----理學檢查呈現生長不良，腹瀉，皮膚紅疹，沒有扁桃腺及淋巴結，但有時可見肝脾腫大
-----頭部X光通常看不到腺狀體，胸部X光通常看不到胸腺陰影
-----感染通常難以控制治癒，多在一歲前死亡
2. Severe combined immunodeficiency (SCID) – ADA
-----可考慮使用ADA酵素補充療法
-----曾有基因治療(合併酵素治療)成功的案例
-----三種細胞(T細胞、B細胞、NK細胞)都缺乏
-----伴有骨骼系統的發育異常，如軟骨發育異常、骨盆畸形、短肢
3. DiGeorge syndrome (congenital thymic aplasia or hypoplasia)
-----chromosome 22有deletion發生，最終造成成熟T細胞數量極少
-----新生兒期發生難以糾正的低血鈣性抽搐，PTH低下
-----chest x-ray發現胸腺不發育
-----合併有大血管異常、先天性心臟病、食道閉鎖、懸雍垂裂、人中短、眼距寬、下頜骨發育不良、耳位低、智力低下
-----血清IgG、IgA、IgM可能正常，但T細胞數量低
4. Hyper-IgM syndrome
-----血清IgM異常升高，可超過11 g/L，但IgG、IgA、IgE低或缺乏
-----常伴有淋巴結腫大、脾腫大、溶血性貧血、腸吸收不良症候群
-----嗜中性球數量下降但T細胞數量與亞群可能正常，血小板低
-----IgM、IgD的B 細胞正常或增加，但IgG、IgA的B細胞缺乏
5. Wiskott-Aldrich syndrome (WAS)
-----X-linked (Xp11.22-11.23), recessive disorder
-----血小板低、血小板體積小、血小板凝集功能差(X-linked thrombocytopenia)
-----抗血小板抗體可能上升
-----容易出血，皮膚容易有嚴重、反覆的濕疹
-----血清IgM低下，IgA、IgE升高，IgG正常或偏低
-----容易反覆細菌感染(lack of IgM production in response to capsular polysaccharide antigens of bacteria)
-----B細胞數正常，但T細胞偏低，CD4細胞數量下降

6. Ataxia-telangiectasia
-----Autosomal recessive
-----進行性小腦ataxia、眼結膜和皮膚微血管擴張
-----AFP升高，可有性腺發育不良、肝功能異常、抗胰島素性糖尿病、惡性淋巴瘤
-----血清IgA、IgE、IgG2、IgG4都下降，IgM偏高
-----B細胞數量可能正常，但T細胞數量低
 

吞噬細胞缺損
1. Chronic granulomatous disease (CGD)
-----嗜中性球的nitroblue tetrazolium (NBT)染色還原試驗值、吞噬球化學發光試驗、NADPH氧化酶活性檢查都會下降
-----多為X-linked recessive disorder
-----血清IgG、IgA、IgM、WBC值上升
-----容易反覆嚴重金黃色葡萄球菌等細菌感染，如淋巴結炎、膿腫、骨髓炎
-----可能有肝脾腫大、出現吞噬細胞、巨細胞、色素性脂質形成的肉芽腫病理結果
2. Leukocyte adhesion deficiency (LAD)
-----Autosomal recessive
-----起因於表面重要黏附分子的缺失，造成無效的白血球遷移與吞噬作用
3. Chédiak-Higashi syndrome
-----Autosomal recessive
-----嗜中性球中的溶酶體缺乏
-----皮膚、毛髮、眼底部分白化症，色素細胞有巨大黑色素顆粒
-----血紅素、血小板、嗜中性球都下降，NK細胞功能下降，T和B細胞功能正常
-----反覆化膿性感染，可有肝脾、淋巴結腫大
4. Neutropenia
-----可能出現於嚴重感染後、放化療後、使用免疫抑制劑或類固醇後

補體缺損
Complement component 1 (C1) inhibitor deficiency (hereditary angioneurotic edema)
-----分三型，都為自體顯性遺傳，目前認為位於11q11~11q13.1之間
-----血清C1-INH蛋白與活性低下，血清中C4a, C3a, C5a的濃度大增
-----主要發病的原因是病人先天上缺乏C1-INH造成kallikrein持續活化，間接產生大量的Bradykinin，因而造成病人血管擴張，微血管通透性增加，血管外水分滲出及皮下水腫
-----遺傳性血管性水腫，皮膚、呼吸道、胃腸道受到侵犯
-----抗原抗體複合物(Ag-Ab complex)的清除率也會下降

若根據發生的階段，可以區分為兩種
= defects of lymphocyte maturation
= defects of lymphocyte activation

Defects of lymphocyte maturation
Severe combined immunodeficiency
= X-linked
---Functional deficiencies: Markedly decreased T cells, normal or increased B cells, reduced serum Ig.
---Presumed mechanism of defect: Cytokine receptor common γ chain gene mutations, defective T cell maturation from lack of IL-7 signals.
= ADA, PNP deficiency (autosomal recessive)
---Functional deficiencies: Progressive decrease in T and B cells (mostly T); reduced serum Ig in ADA deficiency, normal B cells and serum Ig in PNP deficiency.
---Presumed mechanism of defect: ADA or PNP deficiency leading to accumulation of toxic metabolites in lymphocytes.
= Other autosomal recessive
---Functional deficiencies: Decreased T and B cells, reduced serum Ig.
---Presumed mechanism of defect: Defective maturation of T and B cells; genetic basis unknown in most cases, may be mutations in recombinase-activating genes (RAG).
B cell immunodeficiencies
= X-linked agammablobulinemia
---Functional deficiencies: Decrease in all serum Ig isotypes, reduced B cell numbers.
---Presumed mechanism of defect: Block in maturation beyond pre-B cells because of mutation in B cell tyrosine kinase.
= Ig heavy chain deletions
---Functional deficiencies: IgG1, IgG2, or IgG4 absent; sometimes associated with absent IgA or IgE.
---Presumed mechanism of defect: Chromosomal deletion at 14q32 (Ig heavy chain locus)
T cell immunodeficiencies
= DiGeorge syndrome
---Functional deficiencies: Decreased T cells, normal B cells, normal or decreased serum Ig.
---Presumed mechanism of defect: Anomalous development of 3^rd and 4^th branchial pouches leading to thymic hypoplasia.
 

Defects of lymphocyte activation
Selective Ig isotype deficiency
---Functional deficiencies: Reduced or no production of selective isotypes or subtypes of Ig (IgA deficiency most common isotype deficiency, IgG3 deficiency most common subtype deficiency); susceptibility to bacterial infections or no clinical problems.
---Presumed mechanism of defect: Defect in B cell differentiation or T cell help; rare cases of homozygous deletions/mutations of Ig constant region genes.
X-linked hyper-IgM syndrome
---Functional deficiencies: Defects in helper T cell-dependent B cell and macrophage activation.
---Presumed mechanism of defect: Mutation in CD40 ligand.
Common variable immunodeficiency
---Functional deficiencies: Variable reductions in multiple Ig isotypes; normal or decreased B cells.
---Presumed mechanism of defect: Defect in B cell activation, usually caused by intrinsic B cell abnormality (nature unknown).
T cell receptor complex expression or signaling defects
---Functional deficiencies: Decreased T cells or abnormal ratios of CD4⁺ and CD8⁺ subsets; decreased cell-mediated immunity.
---Presumed mechanism of defect: Rare cases caused by mutations or deletions in genes encoding CD3 proteins, zeta-associated protein of 70-kD (ZAP-70).
X-linked lymphoproliferative syndrome
---Functional deficiencies: Uncontrolled B cell proliferation in the setting of Epstein-Barr virus infection leading to B cell lymphomas and hypogammaglobulinemia.
---Presumed mechanism of defect: Mutation in the gene encoding the SLAM-associated protein (SAP) adapter molecule, which is normally required for inhibiting signaling by the signaling lymphocytic activation molecule (SLAM).
Defective class II MHC expression: the bare lymphocyte syndrome
---Functional deficiencies: Lack of class II expression and impaired CD4⁺ T cell development and activation; defective cell -mediated immunity and T cell-dependent humoral immunity.
---Presumed mechanism of defect: Mutation in genes encoding transcription factors required for class II MHC gene expression.
Transporter associated with antigen processing (TAP) deficiency
---Functional deficiencies: Lack of class I MHC molecule expression, decreased number of CD8⁺ T cells; susceptibility to bacterial infections.
---Presumed mechanism of defect: Mutation in the TAP genes preventing peptide loading of class I MHC molecules.