Autoimmunity in Wiskott–Aldrich Syndrome: Updated Perspectives

Figures & data

Figure 1 Structure of WAS gene, cDNA transcript, and Wiskott–Aldrich syndrome protein. Lane 1, Wiskott–Aldrich syndrome protein structure; lane 2, WAS cDNA structure and positions; lane 3, WAS gene structure. Variants associated with XLN: L227P, S272P, and I294T.

Abbreviations: PH, pleckstrin homology; EVH1, vasodilator-stimulated phosphoprotein homology; B, basic; CRIB, Cdc42- and Rac-interactive binding; PRR, proline-rich region; V, verprolin; C, central; A, acidic; XLT, X-linked thrombocytopenia; XLN, X-linked neutropenia; WAS, Wiskott–Aldrich syndrome.

Table 1 Frequency of autoimmune manifestations reported in large cohorts of XLT/WAS

Study	Patients, n	Patients with autoimmunity, n (%)	AIHA, n (%)	Autoimmune thrombocytopenia, n (%)	Neutropenia, n (%)	Vasculitis, n (%)	Arthritis, n (%)	Renal disease, n (%)	IBD, n (%)	Alopecia, n (%)	Other, n (%)
Sullivan et al^Citation25	154	61 (40)	22 (14)	–	4 (2.5)	30 (19.4)	32 (21)	Renal disease 18 (12), IgAN 5, CRF 2	5 (3)	(1)	10* (6.4)
Dupuis-Girod et al^Citation33	55	40 (72)	20 (36)	18 (32.7)	14 (25)	16 (29)	16 (29)	2 (3.5)	5 (9)	–	–
Imai et al^Citation34	50	12 (24)	3 (6)	–	–	4 (8)	3 (6)	IgAN 5 (10) CRF 2 (4)	2 (4)	1 (1.8%)	–
Lee et al^Citation35	35	12 (34.2)	6 (17.1)	–	6 (17.1)	–	–	–	–	–	–
Albert et al^Citation36	173 (XLT)	21 (12), 26 events	6/26 events (23)	ITP: 4/26 events (15)	–	3/26 events (11.5)	3/26 events, 11.5	Nephropathy 9/26 (35)	1 (3.8)	1 (3.8)	–
Shin et al^Citation28	47	15 (32)	–	–	–	–	–	–	–	–	–
Chen et al^Citation29	53	14 (26.4)	12 (22.6), DCT^+ 12 (22.6), ICT^+ 6 (11.3)	1 (1.8)	1 (1.8)	–	1 (1.8)	Probable IgAN 1 (1.8)	–	–	ANA^+ 3 (5.6), antiplatelet IgG 1 (1.8)
Elfeky et al^Citation37	34	15 (44)	9 (26.4)	4 (11.7)	–	2 (5.8)	–	–	–	–	–
Jin et al^Citation38	42	15 (32)	–	–	–	–	–	–	–	–	–
Burroughs et al^Citation30	129	32 (25)	10 (8)	19 (15)	7 (5)	2 (2)	1 (1)	Nephritis 1 (1)	2 (2)	1 (1)	–
Haskologlu et al^Citation39	23	3 (9)	–	–	–	Skin vasculitis 3 (9)	–	CRF 3 (9), IgAN 2 (8.6)]	–	–	–
Suri et al^Citation40	95	38 (40)	AIHA 9 (9.5), DCT^+ 9 (9.5)	–	–	Skin vasculitis 9 (9.5), Takayasu arteritis 1 (1)	–	–	–	–	ANA^+ 9 (9.5), GBS 1(1.1), ALPS-like 1 (1.1)

Notes: *Recurrent angioedema 2 (1.2%); uveitis 3 (1.9%); dermatomyositis 1 (0.6%); autoimmune hepatitis1 (0.6%); pyoderma gangrenosum 1 (0.6%); erythema nodosum 1 (0.6%); cardiac vasculitis 1 (0.6%).

Abbreviations: AIHA, autoimmune hemolytic anemia; IBD, inflammatory bowel disease; CRF, chronic renal failure; ITP, immune thrombocytopenic purpura; IgAN, IgA nephropathy; MPGN, membranoproliferative glomerulonephritis; DCT, direct Coombs test; ICT, indirect Coombs test; ANA, antinuclear antibody; GBS, Guillain–Barré syndrome; ALPS, autoimmune lymphoproliferative syndrome.

Table 2 Genetic variants associated with autoimmunity in patients of XLT/WAS

Sr number	Amino acid position	Domain	Type of variant	Variant	Patients, n	WASp expression	WAS clinical score	Autoimmune manifestations	Study
1	8	PH	Deletion G	Exon 1, p.G8fs44*	1	Absent	5		Jin et al^Citation68
2	13		Nonsense	Exon 1, p.R13*	1	Absent	5A		Lee et al^Citation69
					1	Absent	5		Jin et al^Citation68
					1		5A	Leukocytoclastic vasculitis	Suri et al^Citation40
					1		5A	Gastroesophageal reflux with food and drug allergy; developmental delay	Ferrua et al^Citation70
3	16		Deletion ACCA	Exon 1, p.P16Rfs44*	1	Absent	5A	EBV-associated lymphoproliferative disorder	Lee et al^Citation69
4	24		Missense	Exon 1, p.S24F	1	Reduced	2 to 5A		Albert et al^Citation36
					1	Normal	5A		Imai et al^Citation34
				Exon 1, p.S24P	1		5		Jin et al^Citation38
5	28		Deletion C		1	Absent	5		Jin et al^Citation68
6	30		Deletion 3nt (inframe)	Exon 1, p.H30del	1		5A	Colitis; vasculitis; arthritis; lymphadenitis	Braun et al^Citation71
7	31		Missense	Exon 1, p.E31K	1	Absent	2 to 5A		Albert et al^Citation36
					1		5A	Colitis	Braun et al^Citation71
					2	ND; reduced	5A; 5A	Leukocytoclastic vasculitis; Lupus band test positive; AIHA	Suri et al^Citation40
					1	Absent	5A		Castiello et al^Citation54
8	34		Nonsense	Exon 1, p.R34*	1	ND	5A	Vasculitis	Mahlaoui et al^Citation96
					1	Absent	5		Jin et al^Citation68
					1	ND	ND	Hypothyroidism	Suri et al^Citation40
					1	ND		Posttransplant autoimmunity	Bouma et al^Citation57
			Deletion T		1		5A	IBD	Kolluri et al^Citation72
9	36		Deletion TT	Exon 1, p.F36fs36*	3	Absent	5		Jin et al^Citation68
10	39	PH and EVH1	Missense	Exon 1, p.L39P	1	Reduced	1 to 5A/M		Albert et al^Citation36
					1		1/2 to 5A	Vasculitis; arthritis; anti–smooth muscle and other autoantibody–positive	Crestani et al^Citation119
					1	Reduced	5A	ANA-positive, speckled and cytoplasmic	Suri et al^Citation40
12	41		Nonsense	Exon 1, p.R41*	1	Reduced	5A	AIHA; leukocytoclastic vasculitis; primary sclerosing cholangitis	Suri et al,^Citation40 Vignesh et al^Citation73
					1		5A	Allergy; arthritis	Xie et al^Citation74
					1	Absent	5		Jin et al^Citation68
13	45		Missense	Exon 2, p.T45M	3	Reduced (2) and absent (1)	1 to 5A, 2 to 5A (2)		Albert et al^Citation36
					1	Normal	5		Imai et al^Citation34
					1	Absent	5A		Wu et al^Citation75
				Exon 2, p.T45K and p.T45M	1	Reduced	5A		Liu et al^Citation76
				Exon 2, p.T45M	1		1/2 to 5A	Vasculitis; ANA, ANCA, anti–smooth muscle and other autoantibody–positive	Crestani et al^Citation119
			Complex	Exon 2, p.T45fs66*	1		5A	AIHA, neutropenia	Lee et al^Citation35
14	48		Missense	Exon 2, p.T48I	5		5A	HSP; ulcerative colitis; leukocytoclastic vasculitis; amyloidosis; AIT; HSP with IgA nephropathy (2)	Haskoloğlu et al^Citation39
15	56		Missense	Exon 2, p.A56V	1	Reduced	1 to 5A		Albert et al^Citation36
16	58		Missense	Exon 2, p.P58A	1	Reduced	2 to 5A		Albert et al^Citation36
			Deletion C	Exon 2, p.P58fs75*	1	ND	5		Jin et al^Citation68
17	60		Deletion T		2	Absent (1)	5A		Derry et al^Citation9
18	64		Missense	Exon 2, p.W64R	1		5	AIHA; Coombs-positive; IBD; vasculitis, ANA-positive, multiple autoantibody–positive	Crestani et al^Citation119
19	67		Frameshift	Exon 2, p.E67Efs_*	1	ND	5A	IBD	Crestani et al^Citation119
20	68		Deletion of 4aa and frameshift	Exon 2, p.H68fs72*	1	Absent	5		Jin et al^Citation68
21	70		Deletion of 6nt inframe	Exon 2, p.70_71GAdel	1	Absent	5A	AIHA	Mahlaoui et al^Citation96
22	73		Missense	Exon 2, p.C73Y	1	ND	5A	AIHA	Mahlaoui et al^Citation96
				Exon 2, p.C73Y	1	Reduced	5A	AIHA; DCT-positive	Suri et al^Citation40
23	75		Missense	Exon 2, p.V75M	2	Reduced and absent	1 to 5A, 2 to 5A		Albert et al^Citation36
24	76		Deletion A	Exon 2, p.K76Rfs126*	1	Absent	5A/M		Imai et al^Citation34
25	82		Missense	Exon 2, p.S82P	1		5	Renal failure	Kolluri et al^Citation72
26	85		Missense	Exon 2, p.I85H	1		5A	Severe thrombocytopenia; severe eczema	Boztug et al^Citation77
27	86		Missense	Exon 2, p.R86G, p,R86C, p.R86H	1; 1; 3	Reduced; reduced; reduced and absent	2 to 5A; 1 to 5A, 2 to 5A; 1 to 5A and 2 to 5A (2)		Albert et al^Citation36
				Exon 2, p.R86H	1		5A	AIHA; colitis; severe eczema; vasculitis	Braun et al^Citation71
					1	Normal	5A	AIT	Abina et al^Citation78
					3	ND (2) reduced	5A; 5A	Leukocytoclastic vasculitis; AIHA; DCT-positive	Suri et al^Citation40
				Exon 2, p.R86C	1		5A	AIT	Buchbinder et al^Citation79
					1		5A		Pala et al^Citation80
				Exon 2, p.R86A	1		5A		Amarinthnukrowh et al^Citation81
28	88		Missense	Exon 2, p.Y88C	1		2 to 5A		Albert et al^Citation36
29	91		Missense and nonsense	Exon 3, p.Q91H; p.Q91*	1; 1		5A; 5A	AIHA; AIHA	Haskoloğlu et al^Citation39
			Missense	Exon 3, p.Q91A	1		5A	AIT, food or drug allergy	Ferrua et al^Citation70
			Nonsense	Exon 3, p.Q91*	1		3 to 4	Posttransplant autoimmunity	Bouma et al^Citation57
30	97		Nonsense	Exon 3, p.W97*	2	Absent (2)	5 (2)		Jin et al^Citation68
					1		5A	AIHA, vasculitis	Mahlaoui et al^Citation96
			Missense	Exon 3, p.W97C	1		5A		Schindelhauer et al^Citation82
31	99		Complex nonsense and inframe deletion	Exon 3, p.Q99X	1	Absent	5		Jin et al^Citation68
32	106	EVH1	Frameshift	Exon 3, p.V106Cfs121	1		5	Vasculitis; multiple autoantibody–positive; antiphospholipid antibodies; antiplatelet antibody–positive	Crestani et al^Citation119
33	107		Missense	Exon 3, p.Y107S	1		5A	AIHA	Mahlaoui et al^Citation96
				Exon 3, p.Y107C	1	Reduced	5A		Liu et al^Citation76
34	114		Deletion C, deletion T	Exon 3, p.F114fs126* (2)	2	Absent (2)	5; 5		Jin et al^Citation68
			Missense	Exon 3, p.F114I	1	ND	5A	Vasculitis	Mahlaoui et al^Citation96
			Deletion TTC	Exon 3, p.F114fs*	1			Posttransplant autoimmunity	Knight et al^Citation83
35	116		Missense	Exon 3, p.T116P				AIHA; AIT; seminoma	Kolhatkar et al^Citation84
36	117		Deletion T	Exon 3, p.F117fs*126	1		5A	AIHA	Lee et al^Citation35
37	125		Missense	Exon 4, p.G125R	1	Absent	5		Jin et al^Citation68
38	126		Missense	Exon 4, p.L126P	1		5		Jin et al^Citation68
39	128		Missense	Exon 4, p.F128L	2	Absent (1)	5 (2)		Jin et al^Citation68
40	131		Complex missense	Exon 4, p.E131K	1	Absent	5		Jin et al^Citation68
			Missense	Exon 4, p.E131K	1		5A		Derry et al^Citation9
41	132		Deletion of 6nt inframe	Exon 4, p.132_133DEdel	1	Absent	5A/M	AIHA; malignancy	Mahlaoui et al^Citation96
42	133		Missense	Exon 4, p.E133K	1	ND	5		Jin et al^Citation68
					1	Absent	5A		Liu et al^Citation76
					1		5A	Colitis; vasculitis	Marangoni et al^Citation85
					1		5A	AIHA; Colitis	Braun et al^Citation71
							5A	AIHA; IBD; eosinophilic gastritis; multiple food allergies	Glanzmann et al^Citation86
43	134		Missense	Exon 4, p.A134V	1	Affected	5A	Recurrent arthritis; renal disease	Abina et al^Citation78
				Exon 4, p.A134T	1		5A	Colitis	Braun et al^Citation71
44	151		Deletion AG	Exon 4, p.R151fs167*	1	Absent	5		Jin et al^Citation68
			Missense	Exon 4, p.R151T	1		5A	Colitis	Braun et al^Citation71
45	162	SH3	Insertion C	Exon 5, p.P162Tfs*168	3	Absent (1)	5 (3)		Jin et al^Citation68
46	179		Deletion T	Exon 6, p.L179fs260*	1		5		Jin et al^Citation68
			Deletion T	Exon 6, p.L179fs260*	1		5A	Vasculitis; arthritis; IgA nephropathy	Marangoni et al^Citation85
47	187		Missense	Exon 7, p.G187C	1		5A		Derry et al^Citation9
48	190		Splice-site substitution IVS6 variant	c.559+5G>A	2	Reduced and absent	2 to 5A (2)		Albert et al^Citation36
			Splice-site substitution IVS6 Variant	c.559+5G>A	1	Normal	5A		Imai et al^Citation34
49	210		Deletion T	Exon 7, p.S210fs260*	1	Normal	5A	Pancytopenia	Abina et al^Citation78
50	211		Nonsense	Exon 7, p.R211*	1	ND	5A	Leukocytoclastic vasculitis; Hypothyroidism	Suri et al^Citation40
					1	Absent	5		Jin et al^Citation68
					1	Absent	5A		Liu et al^Citation76
					1	Absent	5A		Wu et al^Citation75
51	218		Insertion CGCA	Exon 7, p.P218fs222*	2		5A (2)	AIHA (2)	Lee et al^Citation35
52	224	B	Missense	Exon 7, p.D224G	1	Absent	5A	AIHA	Mahlaoui et al^Citation96
53	246	CRIB	One splice-site substitution: IVS8 variants G>A	*		Absent	5		Jin et al^Citation68
			One splice-site deletion (IVS7-1delG), one splice-site substitution (IVS8+G>C)	*		Absent; absent	5A; 5A		Imai et al^Citation34
54	285		Nonsense	Exon 9, p.E285*	1		5		Jin et al^Citation68
55	297		Nonsense	Exon 9, p.Q297*	1	Absent	5		Jin et al^Citation68
56	303		Frameshift	Exon 9, p.V303fs305*	1		5A	Colitis; vasculitis; lymphadenitis; arthritis	Braun et al^Citation71
57	321	PRR	Nonsense	Exon 10, p.R321*	3	Absent	5 (3)		Jin et al^Citation68
					1		5A	Allergy; developmental delay	Ferrua et al^Citation70
					1		5		Jin et al^Citation38
58	332		Deletion G	Exon 10, p.V332fs444*	1	Reduced	5		Jin et al^Citation68
59	334		Frameshift	Exon 10, p.G334Vfs444*	2	ND	5A (2)	AIHA (2)	Mahlaoui et al^Citation96
60	336	PRR and motif 1	Nonsense	Exon 10, p.K336*	1		5A	Glomerulonephritis	Shigemura et al^Citation87
61	342		Insertion C	Exon 10, p.L342fs494*	1	Reduced	2 to 5A	IgA nephropathy	Lee et al^Citation69
62	353	PRR	Deletion C	Exon 10, p.P353fs444*	1	ND	5		Jin et al^Citation68
63	358		Insertion G	Exon 10, p.G358fs494*	1	Absent	5	Relapsing polychondritis	Adriani et al^Citation118
64	360		Deletion C	Exon 10, p.P360fs444*	1	Absent	5		Jin et al^Citation68
65	362		Deletion 5nt	Exon 10, p.P362fs*	1		5A	AIHA, hemorrhagic vasculitis, migratory joint pain	Trifari et al^Citation88
			Deletion C	Exon 10, p.P362fs444*	1		5		Jin et al^Citation68
66	363		Frameshift	Exon 10, p.G363Afs444*	1	Absent	5A		Mahlaoui et al^Citation96
67	364		Nonsense	Exon 10, p.R364*	1	Reduced	5A	DCT-positive; ALPS-like illness	Suri et al^Citation40
					1		5		Jin et al^Citation68
68	383	PRR and motif 2	Deletion G	Exon 10, p.P383Lfs444*	1	Absent	5A		Liu et al^Citation76
69	384		Deletion C	Exon 10, p.P384fs444*	1	Absent	5		Jin et al^Citation68
70	387	PRR	Deletion T	Exon 10, p.G387fs444*	1	Absent	5		Jin et al^Citation68
71	389		Complex mutation with inframe 18nt deletion and frameshift 49nt insertion		1	Reduced	5A		Liu et al^Citation76
72	397		Deletion C	Exon 10, p.P397Rfs444*	1	Reduced	5A	Guillain–Barré syndrome	Suri et al^Citation40
74	423		Frameshift	Exon 10, p.G432Cfs496*	1	ND		Posttransplant autoimmunity	Bouma et al^Citation57
75	424		Missense	Exon 10, p.G424P	1	Reduced	5A	Skin vasculitis	Abina et al^Citation78
76	425		Insertion G	Exon 10, p.L425fs494*	2	Truncated (2)	5 (2)		Jin et al^Citation68
77	432	V or WH2	Deletion G	Exon 10, p.G432Efs444*	1	Normal		Skin vasculitis	Abina et al^Citation78
			Deletion A	Exon 10, p.G432Gfs444*	1	Absent	5A		Du et al^Citation89
78	452		Frameshift	Exon 11, E452fs494*	1	ND	5A	AIHA	Mahlaoui et al^Citation96
79	477	C	Deletion of 5nt	Exon 11, p.R447Qfs492*	1	Absent	5A		Mahlaoui et al^Citation96
80	485		Insertion TC	Exon 11, p.Q490Efs*	1		5		Jin et al^Citation68
			Missense	Exon 11, p.D485N	1	Reduced	2 to 5A		Albert et al^Citation36
81	490	A	Insertion G	Exon 12, p.Q490Efs*	1		5A		Kolluri et al^Citation73
82	495		Deletion T	Exon 12, p.D495fs*	1	Absent	5		Jin et al^Citation68
83	503		Missense	Exon 12, p.*503A	1		5A		Amarinthukrowh et al^Citation81
Intronic variants
84			Substitution	IVS1-1G>C	1	Absent	5A	EBV-associated lymphoproliferative disorder	Lee et al^Citation69
85			Substitution	IVS2+1G>A	1	ND	5A	AIHA	Mahlaoui et al^Citation96
86			Substitution	IVS2+1G>A	1	ND	5A	AIHA	Mahlaoui et al^Citation96
87			Substitution	IVS2+1G>A	1	Absent	5	AIHA; colitis; growth retardation	Jin et al^Citation68
88			Deletion	IVS3+1 G>T	1			AIHA	Braun et al^Citation71
89			Deletion	IVS6+1 G>T	1			AIHA; AIT; autoimmune neutropenia	Braun et al^Citation71
90			Splice site	IVS6+1	1			Membranoproliferative glomerulonephritis associated with antiglomerular basement-membrane antibody	Boztug et al^Citation77
91			Deletion	Exon 6, c.559 + 11del 12	1		5	Leukocytoclastic vasculitis	Pellier et al^Citation101
92			Substitution	IVS6+2T>G	1		5	AIHA	Jin et al^Citation68
93			Substitution	IVS6+5G>A	1		5		Jin et al^Citation68
94			Substitution	IVS6+5G>A	1	Reduced	5A		Suri et al^Citation40
95			Deletion	IVS7-1delG	1		5A		Pamela et al^Citation35
96			Substitution	IVS7+1G>T	1	Absent	5	AIHA	Jin et al^Citation68
97			Substitution	IVS7+5G>A	1		2 to 5A	Vasculitis; hepatosplenomegaly; allergy	Albert et al^Citation36
98			Deletion	IVS8+1_4 deIGAGT	1			EBV-associated lymphoproliferative disease	Braun et al^Citation71
99			Substitution	IVS8+1G>A	1	Absent	5	Severe lower-limb vasculitis; arthritis	Jin et al^Citation68
100			Deletion	IVS8+1delG	1	Reduced	5A		Du et al^Citation89
101			Substitution	IVS9+1G>C	1		5A		Haskoloğlu et al^Citation39
102			Substitution	IVS9+2T>G	1	ND	5		Jin et al^Citation68
103			Deletion	1337–1338 + 9del in cDNA	1				Ferrua et al^Citation70
104			Substitution	IVS10+1G>A	1				Haskoloğlu et al^Citation39
105			Deletion	c.1453+1 G>C	1	Absent			Abina et al^Citation78
106			Insertion	IVS11c. 118Ins	2		2 to 5A		Jin et al^Citation68
Undefined variants
107			Deletion	735–2A→G in cDNA	1			Food allergy	Ferrua et al^Citation70
108			Deletion	nv(X) (5,721, 11,840)	1			Recurrent arthritis; vasculitis, Henoch–Schönlein purpura with nephritic-nephrotic syndrome; panuveitis; Crohn’s-like enterocolitis; perianal fistulae and abscesses; pyoderma gangrenosum	Ferrua et al^Citation70
109			Deletion	c.1296delA	1	Absent	5A		Du et al^Citation89
110			Deletion	c.1177delG	1	Absent	5A		Du et al^Citation89
111			Deletion	c.709delC	1		5A	AIHA	Fillat et al^Citation90
112			Deletion	Exon12, 1509A→T in cDNA (rs1289921805)	1			Colitis or gastrointestinal bleeding, mucosal bleeding, suspected food allergy	Ferrua et al^Citation70
113			Deletion	Exon 10, 1595del, proximal breakpoint (5247_6842del) in genomic DNA	1			Food allergy, hepatomegaly, splenomegaly, inflammatory lymphadenopathy; eosinophilia	Ferrua et al^70

Notes: Transcript ENST00000376701.5 for protein positions.*Translational termination (stop) codon.

Abbreviations: AIHA, autoimmune hemolytic anemia; AIT, autoimmune thrombocytopenia; ALPS, autoimmune lymphoproliferative syndrome; ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; ASMA, anti–smooth muscle antibody; EBV, Epstein–Barr virus; DCT, direct Coombs test; IBD, inflammatory bowel disease; ND, not done.

Figure 2 Variants reported in patients of XLT/WAS with autoimmunity. Secondary structure of WASp: α-helix (purple) and β-strands (green)., CDS, coding sequence; PH, pleckstrin homology; EVH1, vasodilator-stimulated phosphoprotein homology; B, basic; CRIB, Cdc42-and Rac-interactive binding; PRR, proline-rich region; V, verprolin; C, central; A, acidic; . Reported variants: deletions (red), missense (yellow), nonsense (blue), insertions (green), splice site (pink), complex and undefined frameshift variants (black).

Table 3 Clinical profile, treatment, and outcomes of patients with autoimmunity in XLT/WAS

Study	Autoimmune manifestations	Mean age at onset (months)	Investigations	Treatment	Outcomes
Sullivan et al^Citation25	Total patients with autoimmunity 61/154, 39.6% AIHA: 22/154, 14.2% Vasculitis: 20/154, 12.9% Renal disease: 18/154, 11.6% Transient arthritis: 17/154, 11% Chronic arthritis: 15/154, 9.7% HSP: 8/154, 5.1%; IBD: 5/154, 3.2%; Dermatomyositis: 1/154, 0.6% Other*: 14/154, 9%	–	Impaired antibody response Diphtheria (58%); tetanus (62%); polio (50%); measles (0); mumps (50%); rubella (33%); pneumococcus (69%) Serum immunoglobulin Variable, no correlation of immunoglobulin levels with autoimmunity	–	Autoimmunity: Poor prognostic marker Predisposition to malignancy: More chance of developing malignancy, ~75% of reported malignancies occurred in patients with autoimmunity
Dupuis-Girod et al^Citation33 2003. France	Total patients with autoimmunity 40/55, 72.7% AIHA: 20 (36.3%); Neutropenia: 14 (25.4%) Arthritis: 16 (29%); Severe thrombocytopenia: 18 (32.7%); Skin vasculitis: 12 (21.8%) Cerebral vasculitis: 4 (7.2%) IBD: 5 (9%); Renal disease: 2 (3.6%)	AIHA: 13.7 Neutropenia: 23.8 Arthritis: 45.3 Skin vasculitis: 53 Cerebral vasculitis: 52 IBD: 39.2 Renal disease: 7	High IgA (28 patients; 50.9%) High IgM (15 patients; 27.2%) Low IgM (16 patients; 29%)	AIHA Corticosteroids at 2 mg/kg/day: CR 2, PR 12, ineffective 6 Cyclophosphamide Effective in 1/3 cases used Azathioprine effective in 4/9 cases used HSCT n=19, retransplant in 1 Severe thrombocytopenia (despite splenectomy) Total 18 IVIg: n=18 High-dose steroids: n=12 HSCT: n=14 Other drugs Cyclosporine Effective against skin vasculitis in 8/12 cases, arthritis 10/16 cases, IBD 1 case, renal disease 1 case	Median survival 14.5 years Three of the four (75%) patients with cerebral vasculitis died Overall survival at 16 years of age 38.2% Poor prognostic factors Maintaining platelet counts >20×10^9/L for <5 months after splenectomy (p=0.012) High IgM (14/15 patients, 93%) with high IgM had AIHA, whereas no patients with low IgM had autoimmunity (p=0.02) AIHA RR 2.38 (p<0.04)
Imai et al^Citation34	Total patients with autoimmunity 12/50, 24% Vasculitis: 4/50, 8% Arthritis: 3/50, 6%; IBD: 2/50, 4%; AIHA: 3/50, 6%; IgA nephropathy: 5/50, 10% Chronic renal failure: 2/50, 4% Other: Asthma: 4/50, 8% Food allergy: 4/50, 8%	–	Comparison of WASp-positive and WASp-negative patients Severe eczema: more in WASp-negative patients (p=0.003). High serum IgE: more in WASp-negative patients (p<0.05).	–	Comparison of WASp-positive and WASp-negative patients: Incidence of autoimmune manifestations comparable between groups (p=0.31)
Ozsahin et al^Citation26	Pre-HSCT autoimmunity 17/96 (17.7%) De novo post-HSCT autoimmunity total 19/96, 19.7%	–	–	HSCT with matched sibling donor 7, matched unrelated donor 6, matched related donor 4	Seven of 17 patients had relapse of autoimmune disease after transplant (p=0.06) 7-year EFS in patients who had autoimmunity was 45%, whereas it was 83% in patients with no autoimmunity (p=0.005)
Albert et al^Citation36	Total patients with autoimmunity 21/173, 12.1% Events: 26 Nephropathy: 9/26, 34.6% AIHA: 6/26, 23%; Vasculitis: 3/26, 11.5%; ITP: 4/26, 15.3%; Arthritis: 3/26, 11.5%; Colitis: 1/26, 3.8%.	Median age 12.2 (4.9–56) years	–	Conservative management	No significant difference in EFS observed with respect to level of WASp expression, IVIg prophylaxis, or antibiotics prophylaxis
Chen et al^Citation29	Total patients with autoimmunity 14 (26.4%) AIHA: (n=12, 22.6%) (two cases had AIHA at diagnosis) ITP: 1 (1.8%) Neutropenia: 1 (1.8%) Arthritis: 1 (1.8%) Renal injury: 1 (1.8%)	AIHA: 17.5 (4–98 months) Arthritis: >8 years Renal injury: > 8 years	Positive DCT in all 12 cases with AIHA; DCT and ICT both positive in 7 cases; Anti-PAIgG (1); ANA (3); low IgM (5); high IgM (1) No significant difference in CD4^+ CD25^+FOXP3^+ Tregs in groups with or without autoimmunity	AIHA Corticosteroids first-line agents (9 of 12 cases), Additional agents IVIg (8) Rituximab (3) Cyclosporine (2) Plasma exchange (2) Tacrolimus (1) Splenectomy (1) CS 5 (42%), PR 4 (33%), no remission in 2 cases (17%) relapse in 1 case (8%) HSCT: For 8 cases of AIHA	Individuals managed conservatively (n=4): 2 died, 50%. Individuals managed with HSCT (n=8): 3 died, 37.5% Post-HSCT: 5 cases had relapses requiring multiple immunosuppressives
Burroughs et al^Citation30	Pre-HSCT autoimmunity Total: n=32, 24.8%; Thrombocytopenia: n=19, 14.7%; Hemolytic anemia: n=10, 7.7%; Neutropenia: n=7, 5.4%; Vasculitis: n=3, 2.3%; IBD: n=2, 1.6%; Arthritis: n=3, 2.3% Nephritis: n=1, 0.8%; Alopecia: n=1, 0.8%. De novo post-HSCT autoimmunity total: 17, 13.2%`	–	–	HSCT	Pre-HSCT autoimmunity outcomes All autoimmune manifestations resolved within ≤1 year of HSCT. Post-HSCT de novo autoimmune illness 13/17 patients responded to immunosuppressive therapy.

Notes: *Recurrent angioedema, neutropenia, cerebral vasculitis, uveitis myositi, autoimmune hepatitis, pyoderma gangrenosum, erythema nodosum, cardiac vasculitis.

Abbreviations: HSCT, hematopoietic stem–cell transplant; HSP, Henoch–Schönlein purpura; AIHA, autoimmune hemolytic anemia; CR, complete remission; PR, partial remission; MSD, matched sibling donor; MUD, matched unrelated donor; MRD, matched related donor; EFS, event-free survival; CB, cord blood; ITP, immunothrombocytopenic purpura; IBD, inflammatory bowel disease; DCT, direct Coombs test; ICT, indirect Coombs test; PAIgG, platelet-associated IgG.

Table 4 Studies reporting posttransplant autoimmunity in XLT/WAS

	Autoimmune manifestations, n (%)	Treatment/outcome
Ozsahin et al^Citation26	Autoimmunity after HSCT Total 19/96, 19.7% Thrombocytopenia: n=10, 10.4% AIHA: n=3, 3% Neutropenia: n=1, 1% Vasculitis: n=2, 2% IBD: n=1, 1% Pericarditis: n=1, 1% Addison’s disease: n=1, 1% Autoimmune thyroiditis: n=1, 1%	Risk factors of autoimmunity after HSCT MUD: 9/32, 28% MRD: 5/19, 26% MSD: 5/45, 11% (p=0.04) Pre-HSCT autoimmunity: 7/17 had persisted autoimmunity after HSCT, though not significant (p=0.06) Mixed/split donor chimerism: p<0.001
Moratto et al^Citation27	Autoimmunity after HSCT 25 (12.7%)	Risk factors for autoimmunity after HSCT Mixed chimerism of T cells (p<0.05) Mixed chimerism of B cells (p<0.05) Mixed chimerism of myeloid cells (p<0.01) No change in posttransplant mortality rate compared to individuals with no autoimmunity
Shin et al^Citation28	Autoimmune cytopenias after HSCT 17 of 31 patients (54.8%) who underwent HSCT after 2000 Bicytopenia: n=8/31 (26%) Cytopenia affecting single cell line: n=8/31 (26%) Pancytopenia: n=1/31 (3%) Most common cytopenia: thrombocytopenia — 13/31, 42%	Median time to develop autoimmune cytopenia 148 (33–467) days Complete resolution (CR) of cytopenia: 11/17, 67%. Median time to achieve CR 1.1 (0.35–2.7) years No role of mixed chimerism in autoimmunity: p=0.5
Chen et al^Citation29	Eight patients with autoimmunity underwent HSCT: five developed autoimmune manifestations after HSCT, three died	Post-HSCT 5 cases had relapses requiring multiple immunosuppressives
Burroughs et al^Citation30	Autoimmunity after HSCT 17 (13.1%) Cytopenias were predominant Hemolytic anemia: n=13, 10% Thrombocytopenia: n=6, 4.6% Neutropenia: n=3, 2.3%	Post-HSCT de novo autoimmune illness 13/17 patients responded to immunosuppressive therapy Risk factors of post-HSCT autoimmunity Pre-HSCT autoimmunity: no risk (p=0.779) MSD: no autoimmunity MUD: 23% risk CB: 9% risk Mixed-edonor chimerism at 6 months: p=0.049

Abbreviations: HSCT, hematopoietic stem cell transplant; AIHA, autoimmune hemolytic anemia; MSD, matched sibling donor; MUD, matched unrelated donor; MRD, matched related donor; CR, complete remission; CB, cord blood.

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