null原发性免疫缺陷病
(primary immunodeficiency,PID)原发性免疫缺陷病
(primary immunodeficiency,PID)陈同辛
上海交通大学医学院附属新华医院
上海儿童医学中心
上海市儿科医学研究所福建省人民医院继续教育学习班原发性免疫缺陷病定义原发性免疫缺陷病定义是指免疫系统的免疫器官,免疫活性细胞(如淋巴细胞、吞噬细胞)及免疫活性分子(免疫球蛋白、淋巴因子、补体和细胞膜表面分子)发生缺陷引起的某种免疫反应缺失或降低,导致机体防御能力普遍或部分下降的一组临床综合症null原发性免疫缺陷病发病率以活产婴计算:1/10000
(1981年日本和1983年澳洲的报道)
(目前认为:1/5000)
香港报道:1/8000(1997年报道)
目前我国大陆尚无统计学报道
按1/10000的发病率,我国每年新出生的2500万新生儿中应有2500个,累计病例至少3~8万
我院30年来(1970年)共发现100多例nullT细胞和B细胞联合免疫缺陷(24)
主要抗体缺陷(16)
其他已明确的免疫缺陷综合征(14)
免疫失调性疾病(15)
吞噬细胞数目、功能先天性缺陷 (26)
天然免疫缺陷(7)
自身炎症性疾病(9)
补体缺陷(23)原发性免疫缺陷病分类(八大类134种)Primary immunodeficiency diseases: An update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol 2007;120:776-94.null以抗体缺陷为主的体液免疫缺陷(50%)
联合免疫缺陷(20%)
吞噬细胞数量和功能缺陷(18%)
以T淋巴细胞缺陷为主的细胞免疫缺陷(10%)
补体缺陷(2%)
免疫缺陷伴其它重要特征
免疫缺陷伴随或继发于其它先天性或遗传性疾病原发性免疫缺陷病分类(七大类)Report of a WHO scientific group: Primary immunodeficiency diseases. Clin Exp Immunol, 1997, 109(suppl 1):1-28null以抗体缺陷为主的体液免疫缺陷(10)
联合免疫缺陷(14)
吞噬细胞数量和功能缺陷(12)
以T淋巴细胞缺陷为主的细胞免疫缺陷(9)
补体缺陷(16)
免疫缺陷伴其它重要特征(3)
免疫缺陷伴随或继发于其它先天性或遗传性疾病(41)原发性免疫缺陷病分类(106种)Report of a WHO scientific group: Primary immunodeficiency diseases. Clin Exp Immunol, 1997, 109(suppl 1):1-28nullFigure 1 The number of ascertained cases with PID per five years in Shanghai Xinhua hospital. nullFigure 2 The spectrum of PID cases ascertained in Shanghai Xinhua hospital and Children Medical Center between 1974 and 2003 according to a modified WHO classification of PID.null一年中有8次以上中耳炎
一年中有2次以上严重鼻窦炎
一年中有2次以上肺炎
在非常见部位发生深部感染2次以上
反复发生深部皮肤或脏器感染
需要应用静注抗生素才能清除感染
非常见或条件性致病菌感染
家庭有PID病史者原发性免疫缺陷病预警症状病史Cooper MA, et al. primary immunodeficiencies. American Family Physician (http://www.aafp.org/afp), 2003, 68(10): 2001-2008 null生长发育仃滞
缺乏淋巴结或扁桃体
皮肤病变:毛细血管扩张、出血点、皮肤霉菌、红斑性狼疮样皮疹
共济失调
一岁以后出现的鹅口瘡
口腔溃疡症状原发性免疫缺陷病预警症状Cooper MA, et al. primary immunodeficiencies. American Family Physician (http://www.aafp.org/afp), 2003, 68(10): 2001-2008 null实验室检查:血清免疫球蛋白 IgG,IgM,IgA(B细胞功能)
CD3,CD4,CD8 (T细胞亚群)
CD19( B细胞数量)
CD56/16( NK 细胞 )
白细胞计数或四唑氮兰试验( NBT吞噬功能)
补体nullIgG亚类(1~4)
胸腺:X 线检查
细胞因子: IL-2,IL2R,IFN,IFNR
细胞表面分子:CD18
基因检测:BTK ,CD40L,WASPnull以抗体缺陷为主的体液免疫缺陷1. X-连锁无丙种球蛋白血症
2. 非X-连锁高IgM血症
3. 普通变异性免疫缺陷病
4. 婴儿暂时性低丙种球蛋白血症
5. 非X-连锁无丙种球蛋白血症6. 选择性IgG亚类缺陷
7. 选择性IgA缺乏症
8. Ig重链缺失
9. appa链缺陷
10. 抗体反应缺陷Report of a WHO scientific group: Primary immunodeficiency diseases. Clin Exp Immunol, 1997, 109(suppl 1):1-28null摘自Nature Immunology,2004,5(1):23-30IgG B-B+Btk-Btk+IgM↑IgMFigure3 Primary B cell immunodeficienciesnull又称Bruton病(1952年)
与编码Bruton tyrosine kinase(btk)基因突变有关 (1993年)
B细胞发育信号传导障碍,B细胞分化受阻,成熟B细胞减少
突变的形式多样,目前文献报道有118种以上X连锁无丙种球蛋白血症( XLA)null几乎无生成抗体能力,各类Ig水平均降低(IgG < 2g/L)
外周血B细胞显著降低( < 0.5%)
外周血T细胞数量和功能正常
Btk基因缺陷,基因定位于Xq21.3-22位置免疫学特征(B- Ig T+ NK+)nullTable1. Clinical features of the suspected X-linked agammaglobulinaemia patientsPatient No.
P1
P2
P3
P4
P5
P6
P7Age of onset
16y
4m
10m
1y
6m
3y9m
1mAge at diagnosis
17y5m
9y
2y
15y
1y
3y19m
4yFamily history
(–)
(+)
(–)
(–)
(+)
(–)
(–)CD19+ B cells
0.1%
0%
0%
1.0%
2.4%
0.05%
1.0% IgG IgA IgM
2.67 <0.10 <0.10
1.94 <0.67 <0.18
<0.45 <0.25 0.20
1.41 0.22 0.24
0.44 <0.245 <0.165
0.82 <0.245 0.43
1.49 0.22 0,17Ig level (g/L-1) at presentation+, history of maternal male relatives who died in early childhood from infection
y, year
m, monthnullTable2. Summary of mutations in the Bruton tyrosine kinase gene of the X-linked agarmmaglobulinaemia patientsPatient No.
P1
P2a
P3a
P4
P5
P6
P7Exon/Intron
Ex 2
Ex 10
Int 17
Ex 15
Int 17
Ex 15
Ex 8cDNA mutation
214C > T
989_999delTGACTCGGAGTinsGGTGGTATTCCAAA
IVS17+1G > A
1658T > C
IVS17-1G > C
1690C > T
786-787delGCodon change
R28C
MTRS286_289RWYSK
Aberrant splicing
M509T
Aberrant splicing
R520X
V219fsX228Mother status
carrier
carrier
carrier
carrier
carrierBTK domain
PH
SH2
SH1
SH1
SH1
SH1
SH3The cDNA nucleotide position corresponds to the sequence reported by Vetrie et al. (1993),
GenBank accession X58957.
a, novel mutation.null与婴儿暂时性低丙种球蛋白血症鉴别特征
年龄
IgM
IgG
IgA
分子缺陷
B细胞
IgG替代?XLA
先天(>6mo)
低
缺如/低
缺如/低
B细胞酪氨酸激酶
缺如/低
是婴儿暂时性低丙球血症
1~2岁
正常
低
正常
未明
存在
不Pediatric Clinics of North America, 47(6): 1241null病因不同、主要影响抗体合成
男女均可发病
起病于任何年龄的反复感染(以细菌感染为主)
胃肠道疾病高发(如慢性兰氏贾弟鞭毛虫病)
易伴发自身免疫性疾病 (如溶血性贫血、恶性贫血、血小板减少等)
淋巴网状内皮系统增生及胃肠道恶性肿瘤高发常见变异型免疫缺陷病(CVID)null与XLA鉴别特征
年龄
IgM
IgG
IgA
分子缺陷
B细胞
T细胞
IgG替代?XLA
先天(>6mo)
低
缺如/低
缺如/低
B细胞酪氨酸激酶
缺如/低
正常
是CVID
任何年龄
正常/低
低
缺如/低
未明
存在
正常或CD4+细胞异常
是Pediatric Clinics of North America, 47(6): 1241nullX-连锁低丙种球蛋白血症伴生长激素缺乏症
X-linked hypogammaglobulinemia with growth hormone deficiency)又称原发性生长激素缺乏症Ⅲ型
多数为非Btk基因突变,可能与多位点基因缺陷有关,如相关基因的连续性缺失(Xq21.3-q22)
但至少已发现多例(5例)为Btk基因突变所致,其生长激素缺乏的原因尚不清楚
生长激素缺乏伴有低丙种球蛋白血症,骨龄延迟 nullACTH<10pg/ml。
垂体CT扫描未见明显异常。
性激素基础值LH<0.1mIU /ml,FSH 0.3 mIU /ml,PRL 8.8ng/ml,E2<20ng/dl,T<20ng/dl,P 0.3 ng/ml。
精氨酸激发试验:GH峰值为6.0ng/ml。
胰岛素激发试验:GH峰值为8.8ng/ml。
IGF1:163ng/ml,IGFBP3:2473.5ng/ml。姚仲达,男,9岁个月(1998年3月2日出生)
反复感染的病史,哥哥Ig13岁死亡
身高:123cm,体重:21kg。 正常男性
9
岁腕骨骨龄图Fig x. Molecular Diagnosis of XLA in Patient (Yao Zhongda) BTK gene PCR direct sequencing Lymphocytic phenotypes: CD3+ 86.88%↑, CD4+ 44.61%,CD8+ 38.14%,CD4/CD8 1.17,CD56+CD16+ 10.47%,CD19+ 0%↓
Immunoglobulin: IgG <0.08g/L↓, IgA <0.28g/L↓, IgM <0.17g/L↓
PCR amplified for each exon for sequencing
X-linked substitution (nonsense) mutation in exon 12, 1114C>T
CAA (Gln)>TAA (stop codon), Q328X
known mutation
mother is heterozygous carrierMolecular Diagnosis of XLA in Patient (Yao Zhongda) BTK gene PCR direct sequencing PatientMothernullBoy, 13 years old
Recurrent respiratory infection
Baldhead
Figure 4. Photo of a patient with CVID: T+ B+ NK+ Ignull卓李伟, Boy, 10years old, recurrent otitis media and pneumonia, arthralgia and articular swellingFigure 5. Photo of a patient with XLA: B- Ig T+ NK+null男,21岁
反复顽固性腹泻
营养不良
强的松治疗6个月后
腹泻缓解
体重恢复正常Figure1 1例CVID伴克隆氏病患者激素治疗前后的照片(T+B+NK+Ig)nullFigure 1. A patient with XLA was complicated by polio after inoculating Poliovirus vaccine (卢新予)男,12岁,河北承德
XLA:T+B-NK+Ig
出生12个月第4次接种脊髓灰质炎疫苗后3d出现发热,
肌注青霉素8天后出现行走困难、右腿不能动,后慢慢恢复,
2个月后出现右测股四头肌萎缩。
平素反复感染,1-2次/月感冒或肺炎。nullX-连锁遗传或常染色体隐性遗传
临床表现为早期反复的严重霉菌、细菌和病毒感染
有时新生儿期麻疹样皮疹可能是唯一症状(GVHD)
多在1岁内死于严重感染严重联合免疫缺陷病(SCID)nullT- B+NK-Ig↓X-连锁遗传(约占总病例50%~60%):IL-2、IL-4、IL-7、IL-9和IL-15共有受体链(c)基因突变
常染色体隐性遗传:JAK3基因突变,JAK3编码一种酪氨酸蛋白激酶,参与c所启始的信号传递nullc is an essential component of the high affinity cytokine receptors for interleukin (IL)-2, -4, -7, -9 and -15. Upon activation of these receptor complexes by cytokine, the JAK3 molecule, which binds selectively to c, is itself activated and subsequently phosphorylates STAT5 (Signal Transducer and Activators of Transcription). Phosphorylated STAT5 dimerises and then translocates to the nucleus where it binds to specific sites to initiate transcriptional events.
the c/JAK3 signalling pathway
摘自 J Clin Pathol 2000; 53:60-65nullFigure 8 photo of a patient with SCID : candida albicans in the mouth男孩,8个月
反复肺炎、鹅口疮
一个舅舅出生后6mo不明原因死亡
T-B+NK-Ig ↓nullFigure 8-2 photo of a patient with SCID : GVHD and BCG vaccination男孩,4个半月
发热,肺炎,肝脾肿大,卡介苗接种后3个月仍留有溃疡,输血后出现皮疹和腹泻nullTable3. Clinical features of the suspected X-linked severe combined immunodeficiency patientsPatient No.
P1
P3
P5Age of onset
2m
10m
6mAge at diagnosis
4.5m
2y
1yFamily history
(–)
(–)
(+) CD19+ cells
638/ L
100%
83.8% IgG IgA IgM
5.38* <0.0667 <0.09
<0.45 <0.25 0.20
0.44 <0.245 <0.165Ig level (g/L-1) at presentation+, history of maternal male relatives who died in early childhood from infection
y, year
m, month
Normal number, T cells: 690-2540/ L; B cells: 90-660/ L; NK cells: 90-590/ L.
*, After IVIGCD3+ cells
1/L
0%
0.3%CD16/56+ cells
35/ L
0%
0.2%Figure1:1例SCID患儿外周血淋巴细胞表型分析CD3+CD8+ 0.66%CD19+ 99.06%CD16+56+ 0.04%Figure1:1例SCID患儿外周血淋巴细胞表型分析nullFigure 1:1例XSCID患儿T细胞和B细胞表面IL-2Rc表达的检测Molecular Diagnosis of X-SCID in Patient 1
IL2RG gene PCR direct sequencingMolecular Diagnosis of X-SCID in Patient 1
IL2RG gene PCR direct sequencing IVS6-17Deletion in patientNormal control: Intron 6 IVS7-11 Deletion in patientNormal control: Intron 7 487bp deletionPatient 1: deletion between Intron 6 and intron 7Deletion mutation from intron 6 to 7 including exon 7 and 2 primer site (IVS6-71 to IVS7-11del487)
Predicted frameshift start at arginine 285 with stop codon (TAA)created at position 342, predicted premature termination (R285fsX342) Carrier diagnosis in IL2RG deletion (XSCID) – Patient 1
PCR-agarose gel electrophoresis Carrier diagnosis in IL2RG deletion (XSCID) – Patient 1
PCR-agarose gel electrophoresis Causative gene: IL2RG in X-chromosome
PCR amplified for each exon for sequencing
No PCR product for amplification of exon 6, 7 and 8
Suspected large deletion, try other primer pairs combination
Deletion mutation including exon 7 and 2 primer site found (IVS6-71 to IVS7-11del487)
Mother diagnosed as heterozygous carrier by PCR directlyMolecular Diagnosis of X-SCID in Patient 2
IL2RG gene PCR direct sequencingMolecular Diagnosis of X-SCID in Patient 2
IL2RG gene PCR direct sequencingPCR amplified for each exon for sequencing
Deletion of “CA” with insertion of “G” found in Exon 3, 310-311CA>G
Predicted frameshift start at histine 104 and stop codon (TAA) created at position 146, predicted premature termination, H104fsX146
Pedigree Analysis of X-SCID in Patient 2
Pedigree Analysis of X-SCID in Patient 2
Molecular Diagnosis of X-SCID in Patient 3
IL2RG gene PCR direct sequencingMolecular Diagnosis of X-SCID in Patient 3
IL2RG gene PCR direct sequencingNormal controlPatient from Prof. Chen, 2-2006X-linked substitution missense mutation
in Exon 3, cDNA T385C, codon CTC>CCC,
L124P. Novel mutation compared to
IL2RGbase (last modified 7/6/2005) and
the recent publication.Database Reference
mRNA: NM_000206
Genomic: NC_000023null常染色体隐性遗传:重组酶活化基因(RAG-1和RAG-2)突变,导致T、B细胞表面抗原受体形成障碍
常染色体隐性遗传(约占AR的50%):腺苷脱氨酶(ADA)缺陷T- B-NK+Ig↓null赵仁杰,男,9M。
生后4个月起反复咳嗽,患“肺炎”2次(7M和9M),抗生素治疗效果不佳。体重进行性下降。
体检:营养发育差,左侧腋下可及一2×2cm肿块,质中,无触痛,活动度小。卡介苗接种处红肿,破溃。轻微吸气三凹,双肺呼吸音粗,可闻及中湿罗音及哮鸣音。肝右肋下2.5cm。Fig 1. 1例 T-B-NK+ SCID患儿卡介苗接种后播散和肺感染图片nullFig 2. 1例 T-B-NK+ SCID患儿淋巴细胞亚群变化CD3+CD4+2.83%CD3+CD8+1.70%CD19+5.65%CD16+/56+
83.33%CD3+CD4-3.54%WBC 7.3*109 /L,L 12%, ADA 6 IU/L,血清Ig(输后20d):IgG 5.59g/L↓、IgA 0.55g/L↓、IgM 0.83g/L
淋巴细胞亚群:CD3+ 6.51%、CD4+ 2.83%、CD8+ 1.70%、CD19+ 5.65%、CD16+/56+ 83.33%。 nullBoy, 10 years old
Onset occurred at the age of 5,
recurrent infections
consanguineous parents
An elder brother was died of infections at the age of 3
T-B+Ig+NK+Figure 8 photo of a patient with Purine nucleoside phosphorylase (PNP)Figure1:疑似PNP患儿外周血CD3/CD4/CD8分析Figure1:疑似PNP患儿外周血CD3/CD4/CD8分析Figure2 疑似PNP患儿外周血CD19/CD16+56分析Figure2 疑似PNP患儿外周血CD19/CD16+56分析CD19+ 57.77%CD16+56+ 5.98%null高IgM血症(HIGM)HIGM1:X-连锁遗传(CD40L基因突变)
HIGM2:常染色体隐性遗传(AID基因突变)
HIGM3:常染色体隐性遗传(CD40基因突变)
HIGM4:常染色体隐性遗传(UNG基因突变)nullWhen the communication between activated T cells and B cells is breached (CD40L and CD40 deficiencies) or signaling through the CD40 is impaired (HIGM-ED) B cells are unable to undergo CSR. Intrinsic defects of gene modification events in B cells may also result in HIGM syndromes. Such defects may be due to mutations in the gene encoding the AID protein, a CSR-specific cofactor (AR-HIGM), and mutations of the UNG gene. TRAF, TNF receptor-associated factor; NF-B, nuclear factor- B; NIK, NF- B-inducing kinase; NEMO, NF- B essential modulator; I- B, inhibitor of NF- B; IKK, I- B-kinase; AID, activation-induced deaminase; UNG, uracyl-DNA glycosilase, C, CSR-specific cofactor. Schematic illustration of molecular defects leading to the HIGM syndrome phenotype nullT+CD40L-B+IgM↑IgG↓最常见为X-连锁遗传(70%) ,即Ⅰ型
T细胞CD40L基因突变
体外T细胞活化后T表达CD40L表达减少是诊断的要点之一nullIgMIgG
IgA
IgE感染细胞外病原菌Isotype switch(细胞内病原菌)Figure 10 molecular defect, immunoglobulin phenotypes, and infections in the hyper-IgM syndrom caused by CD40L mutationnullFigure 11 photo of a patient with XHIGM男孩,6岁起病,现21岁
反复呼吸道感染、粒细胞减少
血小板减少nullTable1. Ig secretion of B lymphocytes induced by CD40mAb and cytokinesGroup
HIGM
ControlStimulus
No stimulus CD40mAb CD40mAb+IL-2 CD40mAb+IL-4
No stimulus CD40mAb CD40mAb+IL-2 CD40mAb+IL-4Ig level (g/L10-6)IgG IgM IgA248 377 379 335
202 56 236 490344 2597 2351 2342
949 3551 3964 4245-- -- -- --
369 355 355 675nullnullExon5
cDNA mutation:
672-675delCTCA
Codon change:
L205fsX240
Mother status:
not carrier11319495-1131949411319492-11319495Figure 12 CD40 ligand gene mutations identified in a patient with HIGMnull又称DiGeorge 综合征(1964年)
目前已知80%~90%的Digeorge综合征存在着染色体22q11的微基因缺失
染色体22q11的微基因缺失包括一组疾病,称之为CATCH22综合征胸腺发育不全nullCATCH 22(取共同的病损首位字母)Cardiac defects
Abnormal facies
Thymus hypoplasia
Cleft palate
Hypocalcemia心脏缺陷
面容异常
胸腺发育不良
腭裂
低血钙null胸腺发育不全甲状旁腺发育不全Ⅲ-Ⅳ咽弓发育不良Ⅰ-Ⅱ咽弓发育不良主要表现(四大临床症状)T细胞减少反复感染(病毒感染)低钙血症手足搐搦心血管异常法乐四联征和大血管异常(如主动脉弓中断等)面颅发育异常腭裂、人中短和低位耳等null外周血淋巴细胞计数减少(<1000个/mm3)
CD3+T细胞减少明显
血清Ig正常或减少,而IgE
血钙 、血磷 、甲状旁腺素
X线胸片:胸腺影缺如免疫学特征null男孩
14个月
支气管肺炎
先心病
免疫功能低下
低钙血症
左侧面瘫Figure 6 photo of a patient with DiGeorge syndrom nullFigure 7 chest radiography of a patient with DiGeorge syndrom : thymus hypoplaisa6个月以内的婴儿看到胸腺阴影,一般在10g以上
看不到阴影,多在4g以内预示胸腺发育不良正常胸腺nullFigure 14 photo of a patient 2 with DiGeorge syndrome 饶宜辰,女,2岁,CATCH22综合症:胸腺缺如伴反复呼吸道感染、先心病(室间隔膜部缺损、动脉导管未闭)、特殊面容(小下颌)
WBC 13×109/L、L 18%、G 80%,CD3+ 43.67%、CD4+ 22.78%、CD8+ 17.97
T细胞数:1020个/mm32004-2-15
2004-2-18null免疫缺陷病
SCID
X性联或JAK3缺陷
RAG-1或RAG-2缺陷
Omenn‘s综合症
ADA缺陷
ZAP-70缺陷
Ⅱ型裸淋巴细胞综合症
T、B细胞联合缺陷
PNP缺陷
共济失调毛细血管扩张症
湿疹-血小板减少伴免疫缺陷
选择性T细胞缺陷
DiGeorge综合症总数
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↓T
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↓CD4
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↓CD8
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↓B
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+
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+NK
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+IgG
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IgG2 ↓
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+IgM
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+IgA
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+IgE
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+循环淋巴细胞血清免疫球蛋白表型部分原发性T细胞免疫缺陷的实验室检查改变特征Pediatric Clinics of North America, 47(6): 1257null湿疹-血小板减少伴免疫缺陷综合症(WAS)Wiskott(1937)和Aldrich(1954)发现
X-连锁隐性遗传
WASP基因突变所致造血细胞WASP表达降低,定位在Xp11.22
发病率1/100000(北欧),1/200000(日本)
以免疫缺陷、湿疹、血小板减少为临床表现null出血以消化道出血为多见,为首发症状
血小板减少伴体积变小
激素和IVIG治疗效果差,易复发
免疫学变化:IgM
IgG轻度或正常
IgA、IgE可能
B细胞、T细胞nullA) Domain structure and activation of WASp. In unstimulated cells, WASp assumes an autoinhibited conformation, in which the C-terminal VCA region interacts with the GBD. Binding of Cdc42- GTP, often in conjunction with phosphorylation of WASp tyrosine 291, induces a conformational change, allowing WASp to activate Arp2/3 complex function.
B) Domain structure of WIP.
C) Model of WASp/WIP function at the IS. WASp and WIP are present in an obligate heterodimer generated by interaction of their N- and C-termini, respectively. WASp recruitment is mediated by the adapters SLP-76 and Nck, bringing it into proximity with Cdc42-GTP and Src kinases in the TCR signaling complex. Independent interaction of WIP with the TCR signaling complex (not shown) occurs through binding to ZAP-70 and CrkL. WIP and WASp likely function coordinately, with WASp activating Arp2/3-complex-induced actin polymerization and WIP stabilizing actin filaments and perhaps also facilitating polymerization.
Regulation of Cytoskeletal Dynamics at the Immune Synapse: New Stars Join the Actin Troupe [J]. Traffic, 2006, 7: 1451–1460.Schematic representation of WASP/WIP complex functionnullWiskott Aldrich Syndrome Patient Photothrombocytopenic purpura eczema nullWAS (Jun-nan Xie)nullnullFigure 1 WAS患者淋巴细胞、血小板扫描电镜图(8000)
A:正常淋巴细胞表面微绒毛密集、细长
B:WAS患者淋巴细胞表面微绒毛稀少、粗短及微绒毛中断样改变
C:正常血小板直径2-4,表面有微绒毛突起
D:WAS患者血小板小(直径1.8)、微绒毛缺乏。(左侧为微绒毛缺乏的“光头淋巴细胞”)ABCDnullnullnull75.01%2.06%NormalPatientFig2 WASP expression deficiency in a patient with WASMolecular diagnosis-WAS-021
genomic PCR-sequencing results – duplication mutationMolecular diagnosis-WAS-021
genomic PCR-sequencing results – duplication mutationX-linked duplication mutation in exon 7, 13 bases duplication causing insertion of "CAGCACCTGGACC" at nucleotide position 693-694 according to GenBank report U12707 (mRNA). frameshift start at Proline 220, stop codon (TAG) created at position 225. Novel mutation.李志灿, 681-693dup, P220fsX225李志灿母, carrierOverlapping of normal and
duplicated sequenceDuplicated sequenceMolecular diagnosis-WAS-021
genomic PCR-sequencing results – mismatch in intron 2, polymorphism?Molecular diagnosis-WAS-021
genomic PCR-sequencing results – mismatch in intron 2, polymorphism?李志灿, IVS2+11_12insCC李志灿母, heterozygous IVS2+11_12insCC
100 alleles of normal control
not done. Don’t know the effect
on the splicing.WAS mutation (WAS-016) WAS mutation (WAS-016) Normal controlPatient with X-linked G>C substitution and “A “deletion
in exon 1 of the same allele, [69G>C; 96delA], [G12A; N21fsX44] (谢俊楠) Mother is carrier with both heterozygous mutation in exon 1 of the same allele null共济失调毛细血管扩张症(AT)常染色体隐性遗传病
发病率1/40000-100000
ATM基因突变所致,定位11q22-23
共济失调、眼部和皮肤毛细血管扩张、反复感染、内分泌异常(无第二性征、生长停滞、糖尿病)、恶性肿瘤
IgG正常、IgA/IgE、出现低分子量IgM
CD3、CD4null共济失调毛细血管扩张症患儿图片眼部球结膜毛细血管扩张患儿的外观形态null共济失调毛细血管扩张症患儿图片null共济失调毛细血管扩张症null共济失调毛细血管扩张症黄褐色色素沉着皮肤色素减退神经皮肤综合症(包括神经、皮肤和眼睛异常)null小脑萎缩(沟回变浅、变宽)中耳炎、鼻窦炎(积水)共济失调毛细血管扩张症null高IgE综合症常染色体隐性或显性遗传病
病因不明,2006年发现Tyk2基因突变,2007年发现STAT3基因突变
牙齿异常、头面部畸形、骨骼异常、金黄色葡萄球菌感染、皮肤损害
血清IgE异常增高>20000IU/ml
CD45RO↓、IL-4↑、IFN-γnull 张菊,女,15岁,安徽省寿县人 。
病史:患儿于学龄前,反复肺炎约10次/年。学龄期后至今约5-6次/年。抗感染治疗前后肺部均罗音均持续存在。易反复发生皮肤化脓性感染,主要发生于面部,气温高时较明显,伴搔痒,破溃后有脓液流出。
7个月时,发现先天性右侧髋关节脱位,行支架固定术
胸片示右下肺大泡?右下肺囊肿?。
6-7岁时,因咳嗽伴淡血性脓痰,行右下肺囊肿切除术
10岁时,因咳嗽,咳脓痰半月伴间歇发热,行胸部CT示左上肺大泡,右下肺肺脓肿。
4-5个月时,面部出现小泡样皮疹其中含有脓液,主要位于面部及前臂,躯干部少许。
6-7岁时,头皮可及脓疮其中含有较多脓液。nullnull免疫细胞表型 :CD3 81.17%↑、CD4 41.66%↑、
CD8 36.59%↑、CD19 12.07%、NK 2.51%↓,
血清免疫球蛋白:IgG 15.1g/L、IgA 1.51g/L、IgM 1.6g/L、
IgE 22000IU/ml↑血常规:WBC 8.4*10^9/L,N 48%,L 47%,MEOS 0%,MMO 5%,
HGB 127g/L,BPC 281*10^9/LTh1/Th2表达CD45RA/CD45ROCD40L表达Figure1:1例高IgE血症患儿免疫功能变化nullX连锁淋巴组织增殖性疾病(XLP)1969年Hamble等首先报道
1990年证明致病基因XLP定位于Xq25
发病率1~3:1000000
为联合免疫缺陷,EBV感染可加重该病的病程—致死性IMnullXLP临床表现的5种类型爆发性传染性单核细胞增多症伴有病毒相关的噬血综合症(VAHS)(~58%)
丙种球蛋白异常(~31%)
淋巴组织增生性恶性肿瘤(~31%)
再生障碍性贫血(~3%)
血管和肺部淋巴瘤样肉芽肿(~3%)null成彦杰,男,3岁11月,浙江省义乌市人
迁延性重症肺炎、急性暴发性心肌炎、颅内感染、呼吸循环衰竭
患儿一姨表兄2岁6个月时因“暴发性EBV感染”死亡;患儿母亲一姨表兄2岁时因“败血症”死亡;患儿母亲一舅舅13岁时因脚部感染死亡; IgG:3.95g/L↓
IgA:4.29g/L↑
IgM:1.84g/L
CD3+ 56.86%、CD4+ 36.14%、CD8+ 18.34% null(a) B cells present Ag in the context of MHC class II complexes to the TCR (1). In the presence of appropriate accessory signals (e.g., interaction between B7 molecules on B cells and CD28 on T cells), the T cells become activated (1). This results in the induction of expression of CD40L and ICOS, and an increase in SAP expression in the T cells (2). The interaction between CD40L on T cells and CD40 on B cells facilitates activation and Ig production by B cells (3). Signals delivered through ICOS by ICOSL (3) induce IL-10 secretion, which contributes to Ig production. Because the phenotype of ICOS deficiency resembles that of sap / mice and XLP patients, we hypothesize that interactions between SAP-associating SLAM family receptors on TFH cells and B cells (e.g., CD84, Ly9, NTB-A) facilitate maximal expression of ICOS. (b) In the absence of SAP, ICOS expression on T cells is lower, resulting in insufficient signals for optimal B cell activation, causing impaired B cell differentiation, as evidenced in vivo by deficiencies in memory B cells and plasma cells and hypogammaglobulinemia.Figure 1 Impaired B cell differentiation in XLP may result from impaired ICOS expression and IL-10 production by CD4+ T cells.nullXLP patients have been found to have impaired development of memory B cells, long-lived plasma cells, and NKT cells, as well as defects in the function of CD4+ T cells (reduced production of IL-10 and expression of ICOS), CD8+ T cells (cytotoxicity against EBV-transformed B cells