CTLA4

Summary

CTLA4 (cytotoxic T-lymphocyte associated protein 4, HGNC:2505) is a protein-coding gene on chromosome 2q33.2, encoding Cytotoxic T-lymphocyte protein 4 (P16410). Inhibitory receptor acting as a major negative regulator of T-cell responses.

This gene is a member of the immunoglobulin superfamily and encodes a protein which transmits an inhibitory signal to T cells. The protein contains a V domain, a transmembrane domain, and a cytoplasmic tail. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. Mutations in this gene have been associated with insulin-dependent diabetes mellitus, Graves disease, Hashimoto thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, and other autoimmune diseases.

Source: NCBI Gene 1493 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 45
• Clinical variants (ClinVar): 303 total — 44 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 181
• Druggable target: yes
• MANE Select transcript: NM_005214

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2505
Approved symbol	CTLA4
Name	cytotoxic T-lymphocyte associated protein 4
Location	2q33.2
Locus type	gene with protein product
Status	Approved
Aliases	CD152, CD, GSE, CTLA-4
Ensembl gene	ENSG00000163599
Ensembl biotype	protein_coding
OMIM	123890
Entrez	1493

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000295854, ENST00000427473, ENST00000487393, ENST00000648405, ENST00000650075, ENST00000696049, ENST00000696479

RefSeq mRNA: 2 — MANE Select: NM_005214 NM_001037631, NM_005214

CCDS: CCDS2362, CCDS42803

Canonical transcript exons

ENST00000648405 — 4 exons

Exon	Start	End
ENSE00003548810	203870586	203870933
ENSE00003965892	203872708	203873965
ENSE00003965893	203871378	203871487
ENSE00003967479	203867771	203868051

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 87.62.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 5.9324 / max 1232.3727, expressed in 169 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
24779	3.0857	121
24781	2.1789	108
24780	0.4781	60
24782	0.1897	48

Top tissues by expression

261 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lymph node	UBERON:0000029	87.62	gold quality
vermiform appendix	UBERON:0001154	84.08	gold quality
buccal mucosa cell	CL:0002336	83.44	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.82	gold quality
epithelial cell of pancreas	CL:0000083	80.77	silver quality
caecum	UBERON:0001153	80.12	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.21	gold quality
granulocyte	CL:0000094	77.13	gold quality
pancreatic ductal cell	CL:0002079	75.87	gold quality
superficial temporal artery	UBERON:0001614	74.64	gold quality
gall bladder	UBERON:0002110	74.43	gold quality
tonsil	UBERON:0002372	73.71	gold quality
rectum	UBERON:0001052	73.08	gold quality
spleen	UBERON:0002106	72.07	gold quality
blood	UBERON:0000178	71.38	gold quality
epithelium of nasopharynx	UBERON:0001951	70.89	gold quality
myocardium	UBERON:0002349	70.71	gold quality
small intestine Peyer’s patch	UBERON:0003454	70.22	gold quality
oocyte	CL:0000023	69.07	gold quality
right lung	UBERON:0002167	68.56	gold quality
small intestine	UBERON:0002108	67.64	gold quality
mucosa of paranasal sinus	UBERON:0005030	67.52	gold quality
mucosa of transverse colon	UBERON:0004991	67.50	gold quality
nasal cavity epithelium	UBERON:0005384	67.44	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	67.42	gold quality
vena cava	UBERON:0004087	66.91	gold quality
upper lobe of left lung	UBERON:0008952	66.32	gold quality
quadriceps femoris	UBERON:0001377	66.01	gold quality
upper lobe of lung	UBERON:0008948	65.83	gold quality
tibialis anterior	UBERON:0001385	65.76	silver quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-HCAD-29	yes	2750.29
E-CURD-89	yes	525.47
E-CURD-88	yes	374.45
E-CURD-122	yes	340.29
E-CURD-120	yes	51.21
E-CURD-46	yes	25.51
E-ANND-3	yes	5.98
E-CURD-112	no	3.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, ESR1, FOXO1, FOXP3, GATA3, IRF8, LEF1, MSC, NFATC2, NR3C1, NR5A1, RUNX1, USF1, USF2

miRNA regulators (miRDB)

69 targeting CTLA4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-3910	99.95	71.13	2227
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-154-3P	99.50	70.05	831

Literature-anchored findings (GeneRIF, showing 40)

• CTLA4 gene polymorphisms are associated with, and linked to, insulin-dependent diabetes mellitus in a Russian population. (PMID:11286636)
• effect on cytokine production by antigen-stimulated T cells (PMID:11751964)
• CTLA4 gene region is associated with genetic susceptibility to celiac disease in UK families. (PMID:11826026)
• The B7-CD28/CTLA-4 costimulatory pathway has a dominant role in regulating T-cell activation. Antagonists enable graft survival and suppress autoimmunity. (PMID:11826754)
• results suggest that the CTLA-4 gene region on chromosome 2q33 is a susceptibility locus for autoimmune hypothyroidism in the United Kingdom (PMID:11842815)
• The CTLA-4 49 Ala allele confers an increased risk of type 1 diabetes, independent of age and HLA-DQ genetic markers (PMID:11900275)
• the strongest association between CTLA4 gene polymorphisms and RA susceptibility occurs with the 3’ UTR polymorphism (PMID:11916172)
• results support the concept that CTLA-4 plays a critical role in the autoimmune process in Graves’ disease (PMID:11936461)
• polymorphism in type 1 diabetics in a Romanian population (PMID:12003670)
• CTLA-4 gene polymorphism contributes to the genetic risk for latent autoimmune diabetes in adults. (PMID:12021137)
• Surface cytotoxic T lymphocyte-associated antigen 4 partitions within lipid rafts and relocates to the immunological synapse under conditions of inhibition of T cell activation. (PMID:12021313)
• association of Wegener’s granulomatosis (WG) with 2 single nucleotide polymorphisms (SNP), a +49 A/G polymorphism in coding sequence (CDS) 1 and a C/T base exchange in the promoter region at position -318. (PMID:12022356)
• Long-term therapy with recombinant human erythropoietin decreases percentage of T-cells in primary glomerulonephritis haemodialysis patients. (PMID:12032199)
• evidence against the +49 A/G transition as the aetiological polymorphism within the CTLA4 gene (PMID:12047357)
• segregation analysis supports the hypothesis of a modulation by CTLA-4 49 G/A dimorphism of the susceptibility to type 1 diabetes conferred by maternal HLA-DRB1*03 inheritance (PMID:12047362)
• Remission of Graves’ hyperthyroidism and A/G polymorphism at position 49 in exon 1 of cytotoxic T lymphocyte-associated molecule-4 gene. (PMID:12050220)
• The -318T allele is associated with a higher promoter activity than the -318C allele. (PMID:12058260)
• Cell surface expression of the HIV-1 envelope glycoproteins is directed from intracellular CTLA-4-containing regulated secretory granules. (CTLA-4) (PMID:12060749)
• exon 1 polymorphism of the cytotoxic T lymphocyte antigen 4 gene influences on thyroid antibody production in patients with newly diagnosed Graves’ disease. (PMID:12097196)
• Reduced expression of CTLA-4 may contribute to favorable umbilical cord blood T lymphocyte allogeneic responses (PMID:12135671)
• The results showed that the CTLA4 dimorphism does not affect susceptibility to MS in ethnic Russians, be these stratified or not with regard to DRB1 alleles corresponding to serologic specificities DR1 to DR16. (PMID:12173468)
• Among Filipinos, the CTLA-4 genotypes are associated with type I diabetes only in the presence of the predisposing DR3, 4, and 9 haplotypes (P=0.012). (PMID:12185534)
• role of ligation in modulating TCR-induced transcriptional profiles (PMID:12195015)
• Results suggest that the linkage of the CTLA-4 A49G single nucleotide polymorphism to autoimmune thyroid disease is most likely secondary to linkage disequilibrium. (PMID:12202150)
• HTLV-1 infection is not associated with CTLA-4 polymorphisms in patients with Hashimoto’s thyroiditis (PMID:12225635)
• Levels of sCTLA-4 increase with the serum concentration of antibodies against the acetylcholine receptor. The (AT)(n) polymorphism in the 3’-untranslated region causes decreased mRNA stability and reduced levels of CTLA-4. (PMID:12225905)
• common autoimmunity predisposing signal peptide variant of the cytotoxic T-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele (PMID:12244107)
• CTLA-4 upregulation during aging (PMID:12297345)
• CD80 and CD86 differ in their interactions with CTLA-4 and that CD80 appears to be the preferential inhibitory ligand for CTLA-4 working via a population of CD4(+) CD25(+) CTLA-4(+) regulatory T cells. (PMID:12355442)
• role of genotypes at the -1722 locus in susceptibility to systemic lupus erythematosus (PMID:12384790)
• analysis of expression on leukocytes, hematopoietic cell lines, and a variety of myeloid and lymphoid leukemias (PMID:12393538)
• at least two novel signal pathways regulate CTLA-4 gene expression and CD152 molecule up-regulation in human CD4(+) T lymphocytes, in the absence of full T cell activation (PMID:12444128)
• CTLA4 exon 1 dimorphism is associated with primary progressive multiple sclerosis. (PMID:12458055)
• C-318T and A+49G CTLA4 gene polymorphisms and their haplotypes are not associated in Dutch Caucasian patients with IBD and in Chinese patients with UC. (PMID:12465728)
• In Japanese patients, the +49A allele of CTLA-4 increased in the presence of systemic sclerosis with the anti-RNP antibody. (PMID:12508774)
• Allele G and G/G genotype confer genetic susceptibility to Grave’s disease; (ii) CTLA-4 A49G polymorphism is not associated with the development of Grave’s ophthalmopathy; (iii) different non-genetic factors may contribute to GO in different populations. (PMID:12534352)
• prevalence of the A and G alleles of the CTLA-4 gene in autoimmune hemolytic anemia, AIHA and CLL, and immune thrombocytopenic purpura indicate that the G allele predisposes to the development of AIHA, particularly among patients with CLL (PMID:12555221)
• CTLA-4 is a predisposing gene for celiac disease in an Italian population with a prominent role in patients not carrying the high-risk human leukocyte antigen-DQ2 molecules. (PMID:12559633)
• Length of exposure and microfilarial antigen status are both important factors in determining the level of CTLA-4 expression in filarial infections and may provide insight into its role in diminished parasite antigen-specific T cell responsiveness. (PMID:12574361)
• distinct association exists between the G allele of CTLA-4 and high values of GAD Ab, residual beta-cell function, and the absence of HLA-DRB1*0405. (PMID:12610047)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ctla4	ENSMUSG00000026011
rattus_norvegicus	Ctla4	ENSRNOG00000054129

Paralogs (1): CD28 (ENSG00000178562)

Protein

Protein identifiers

Cytotoxic T-lymphocyte protein 4 — P16410 (reviewed: P16410)

Alternative names: Cytotoxic T-lymphocyte-associated antigen 4

All UniProt accessions (3): P16410, A0A8Q3SIR7, A0A8Q3WKZ2

UniProt curated annotations — full annotation on UniProt →

Function. Inhibitory receptor acting as a major negative regulator of T-cell responses. Acts as a decoy receptor: the affinity of CTLA4 for its natural B7 family ligands, CD80 and CD86, is considerably stronger than the affinity of their cognate stimulatory coreceptor CD28.

Subunit / interactions. Homodimer; disulfide-linked (PubMed:11279501, PubMed:11279502, PubMed:21156796, PubMed:28484017, Ref.24). Interacts with ICOSLG.

Subcellular location. Cell membrane.

Tissue specificity. Widely expressed with highest levels in lymphoid tissues. Detected in activated T-cells where expression levels are 30- to 50-fold less than CD28, the stimulatory coreceptor, on the cell surface following activation.

Post-translational modifications. N-glycosylation is important for dimerization. Phosphorylation at Tyr-201 prevents binding to the AP-2 adapter complex, blocks endocytosis, and leads to retention of CTLA4 on the cell surface.

Disease relevance. Systemic lupus erythematosus (SLE) [MIM:152700] A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Disease susceptibility is associated with variants affecting the gene represented in this entry. Genetic variations in CTLA4 may influence susceptibility to Graves disease, an autoimmune disorder associated with overactivity of the thyroid gland and hyperthyroidism. Type 1 diabetes mellitus 12 (T1D12) [MIM:601388] A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Disease susceptibility is associated with variants affecting the gene represented in this entry. Celiac disease 3 (CELIAC3) [MIM:609755] A multifactorial, chronic disorder of the small intestine caused by intolerance to gluten. It is characterized by immune-mediated enteropathy associated with failed intestinal absorption, and malnutrition. In predisposed individuals, the ingestion of gluten-containing food such as wheat and rye induces a flat jejunal mucosa with infiltration of lymphocytes. Disease susceptibility is associated with variants affecting the gene represented in this entry. Immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL) [MIM:616100] An autosomal dominant primary immunodeficiency characterized by severe autoimmunity, infiltration of non-lymphoid organs, such as the intestine, lungs and brain, by hyperactive T cells and B cells, autoimmune cytopenias, and hypogammaglobulinemia in early childhood. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. Genetic variations in CTLA4 are associated with susceptibility to several autoimmune disorders. They influence responsiveness to hepatitis B virus (HBV) infection [MIM:610424].

Miscellaneous. The therapeutic antibody Ipilimumab competes for the binding site of the endogenous ligands CD80/B7-1, CD86/B7-2 and ICOSLG.

Isoforms (5)

UniProt ID	Names	Canonical?
P16410-1	1	yes
P16410-2	2, ss-CTLA-4
P16410-3	3
P16410-4	4
P16410-5	5

RefSeq proteins (2): NP_001032720, NP_005205* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR008096	CTLA4	Family
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR040216	CTLA4/CD28	Family

Pfam: PF07686

UniProt features (49 total): strand 14, mutagenesis site 8, splice variant 6, disulfide bond 3, region of interest 3, glycosylation site 2, topological domain 2, sequence variant 2, sequence conflict 2, signal peptide 1, chain 1, transmembrane region 1, turn 1, helix 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
7CIO	X-RAY DIFFRACTION	1.1
9DQ3	X-RAY DIFFRACTION	1.64
3OSK	X-RAY DIFFRACTION	1.8
5GGV	X-RAY DIFFRACTION	2
3BX7	X-RAY DIFFRACTION	2.1
7ELX	X-RAY DIFFRACTION	2.14
7DV4	X-RAY DIFFRACTION	2.38
7SU0	X-RAY DIFFRACTION	2.41
7SU1	X-RAY DIFFRACTION	2.53
2X44	X-RAY DIFFRACTION	2.6
6RP8	X-RAY DIFFRACTION	2.6
8GAB	X-RAY DIFFRACTION	2.72
1I8L	X-RAY DIFFRACTION	3
5TRU	X-RAY DIFFRACTION	3
6RQM	X-RAY DIFFRACTION	3
6XY2	X-RAY DIFFRACTION	3.05
1I85	X-RAY DIFFRACTION	3.2
5XJ3	X-RAY DIFFRACTION	3.2
8HIT	X-RAY DIFFRACTION	3.2
6RPJ	X-RAY DIFFRACTION	3.25
1H6E	X-RAY DIFFRACTION	3.6
1AH1	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16410-F1	79.67	0.48

Antibody-complex structures (SAbDab): 13 — 5GGV, 5TRU, 5XJ3, 6RP8, 6RPJ, 6RQM, 6XY2, 7DV4, 7ELX, 7SU0, 7SU1, 8HIT, 9DQ3

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 201

Disulfide bonds (3): 58–129, 85–103, 157

Glycosylation sites (2): 113, 145

Mutagenesis-validated functional residues (8):

Position	Phenotype
45	strongly reduced interaction with cd80, cd86 and icoslg.
47	strongly reduced interaction with cd80, cd86 and icoslg.
49	strongly reduced interaction with cd80, cd86 and icoslg.
70	strongly reduced interaction with cd80, cd86 and icoslg.
130	strongly reduced interaction with cd80, cd86 and icoslg.
132	strongly reduced interaction with cd80, cd86 and icoslg.
139	strongly reduced interaction with cd80, cd86 and icoslg.
143	strongly reduced interaction with cd80, cd86 and icoslg.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-389356	Co-stimulation by CD28
R-HSA-389513	Co-inhibition by CTLA4
R-HSA-8877330	RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)

MSigDB gene sets: 647 (showing top): GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, AAGCAAT_MIR137, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_B_CELL_ACTIVATION, NKX25_02, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_B_CELL_ACTIVATION, GOCC_CELL_SURFACE, GOBP_B_CELL_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION

GO Biological Process (13): adaptive immune response (GO:0002250), immune response (GO:0006955), DNA damage response (GO:0006974), negative regulation of B cell proliferation (GO:0030889), negative regulation of T cell proliferation (GO:0042130), positive regulation of apoptotic process (GO:0043065), negative regulation of regulatory T cell differentiation (GO:0045590), T cell receptor signaling pathway (GO:0050852), B cell receptor signaling pathway (GO:0050853), negative regulation of T cell receptor signaling pathway (GO:0050860), negative regulation of T cell activation (GO:0050868), immune system process (GO:0002376), regulation of T cell proliferation (GO:0042129)

GO Molecular Function (2): receptor decoy activity (GO:0140319), protein binding (GO:0005515)

GO Cellular Component (7): Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), clathrin-coated endocytic vesicle (GO:0045334), perinuclear region of cytoplasm (GO:0048471), protein complex involved in cell adhesion (GO:0098636), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Regulation of T cell activation by CD28 family	2
Transcriptional regulation by RUNX1	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of lymphocyte proliferation	2
T cell proliferation	2
antigen receptor-mediated signaling pathway	2
regulation of T cell activation	2
cytoplasm	2
cellular anatomical structure	2
immune response	1
immune system process	1
response to stimulus	1
cellular response to stress	1
regulation of B cell proliferation	1
B cell proliferation	1
negative regulation of B cell activation	1
regulation of T cell proliferation	1
negative regulation of T cell activation	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
regulatory T cell differentiation	1
negative regulation of T cell differentiation	1
regulation of regulatory T cell differentiation	1
T cell receptor signaling pathway	1
regulation of T cell receptor signaling pathway	1
negative regulation of antigen receptor-mediated signaling pathway	1
T cell activation	1
negative regulation of lymphocyte activation	1
negative regulation of leukocyte cell-cell adhesion	1
biological_process	1
regulation of lymphocyte proliferation	1
molecular sequestering activity	1
binding	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
clathrin-coated vesicle	1
endocytic vesicle	1

Protein interactions and networks

STRING

3692 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTLA4	CD80	P33681	999
CTLA4	CD86	P42081	999
CTLA4	CD274	Q9NZQ7	999
CTLA4	PDCD1LG2	Q9BQ51	999
CTLA4	ICOS	Q9Y6W8	994
CTLA4	ICOSLG	O75144	993
CTLA4	A0A087X1L8	A0A087X1L8	992
CTLA4	LGALS9	O00182	991
CTLA4	PDCD1	Q15116	990
CTLA4	CD28	P10747	987
CTLA4	CD276	Q5ZPR3	985
CTLA4	PTPN11	Q06124	984
CTLA4	LGALS9B	Q3B8N2	974
CTLA4	LGALS9C	Q6DKI2	974
CTLA4	CD40	P25942	973

IntAct

53 interactions, top by confidence:

A	B	Type	Score
CD80	CTLA4	psi-mi:“MI:0407”(direct interaction)	0.880
CD80	CTLA4	psi-mi:“MI:0915”(physical association)	0.880
CTLA4	CD80	psi-mi:“MI:0407”(direct interaction)	0.880
CTLA4	CD80	psi-mi:“MI:0915”(physical association)	0.880
CD86	CTLA4	psi-mi:“MI:0407”(direct interaction)	0.840
CD86	CTLA4	psi-mi:“MI:0915”(physical association)	0.840
CTLA4	CD86	psi-mi:“MI:0915”(physical association)	0.840
CD86	CTLA4	psi-mi:“MI:2364”(proximity)	0.840
CTLA4	LRBA	psi-mi:“MI:0915”(physical association)	0.670
PIK3R1	CTLA4	psi-mi:“MI:0914”(association)	0.640
CTLA4	MALL	psi-mi:“MI:0915”(physical association)	0.560
TMEM218	CTLA4	psi-mi:“MI:0915”(physical association)	0.560
CTLA4	CTXN3	psi-mi:“MI:0915”(physical association)	0.560
CTLA4	B4GALT5	psi-mi:“MI:0914”(association)	0.530
RAPGEF1	CTLA4	psi-mi:“MI:0915”(physical association)	0.400
CD274	CTLA4	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC10	CTLA4	psi-mi:“MI:0915”(physical association)	0.400
ICOSLG	CTLA4	psi-mi:“MI:0915”(physical association)	0.400
CTLA4	TMEM120B	psi-mi:“MI:0914”(association)	0.350
RAB8A	CTLA4	psi-mi:“MI:0403”(colocalization)	0.270

BioGRID (118): AP2M1 (Co-crystal Structure), CTLA4 (Co-localization), CTLA4 (Co-localization), CTLA4 (Co-localization), CTLA4 (Co-localization), CTLA4 (Two-hybrid), CTLA4 (Two-hybrid), CTXN3 (Two-hybrid), CD80 (Reconstituted Complex), CTLA4 (Co-crystal Structure), CD86 (Co-crystal Structure), SLC25A51 (Affinity Capture-MS), ULBP3 (Affinity Capture-MS), FAR2 (Affinity Capture-MS), UBXN1 (Affinity Capture-MS)

ESM2 similar proteins: A2A7V7, A2TGX5, A5D7B2, G3X8R9, O88875, O95944, P0DMS9, P11912, P12318, P15530, P16410, P22273, P31785, P31994, P31995, P34902, P40259, P50283, Q02242, Q1ERP8, Q2LA85, Q2YFS1, Q2YFS2, Q2YFS3, Q3LRV9, Q3U497, Q566E6, Q5T2D2, Q60513, Q6SJQ0, Q6SJQ5, Q6SJQ7, Q6TYI6, Q6UXG3, Q6UXN2, Q7TSN2, Q86YW5, Q8K558, Q8SPV8, Q8TDQ1

Diamond homologs: O02757, P09793, P10747, P16410, P31041, P31042, P31043, P42069, P42072, Q28071, Q9XSI1, Q9MYX7

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
FYN	unknown	CTLA4	phosphorylation
FYN	“up-regulates quantity by stabilization”	CTLA4	phosphorylation
JAK2	“up-regulates quantity by stabilization”	CTLA4	phosphorylation
LCK	“up-regulates quantity by stabilization”	CTLA4	phosphorylation
LCK	unknown	CTLA4	phosphorylation
ipilimumab	“down-regulates activity”	CTLA4	binding
CTLA4	“down-regulates activity”	AKT
CTLA4	up-regulates	“T cell exhaustion”
TXK	“up-regulates quantity by stabilization”	CTLA4	phosphorylation
hsa-miR-138-5p	“down-regulates quantity by repression”	CTLA4	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
CD28 dependent PI3K/Akt signaling	5	109.4×	2e-07
Constitutive Signaling by Aberrant PI3K in Cancer	5	35.2×	7e-06
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	6	32.3×	2e-06
Signaling by Interleukins	7	24.9×	1e-06
PIP3 activates AKT signaling	6	22.3×	6e-06
Diseases of signal transduction by growth factor receptors and second messengers	6	18.9×	1e-05
Cytokine Signaling in Immune system	7	15.9×	6e-06
Signaling by Receptor Tyrosine Kinases	5	14.3×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of T cell activation	5	119.7×	2e-07
T cell costimulation	5	85.1×	6e-07
adaptive immune response	6	23.0×	2e-05
immune response	5	10.7×	1e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

303 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	44
Likely pathogenic	21
Uncertain significance	136
Likely benign	67
Benign	20

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1029948	NM_005214.5(CTLA4):c.226C>T (p.Gln76Ter)	Pathogenic
1071971	NC_000002.11:g.(?204731519)(204732794_?)del	Pathogenic
1439020	NM_005214.5(CTLA4):c.71_72del (p.Leu24fs)	Pathogenic
1449408	NM_005214.5(CTLA4):c.238C>T (p.Gln80Ter)	Pathogenic
161109	NM_005214.5(CTLA4):c.151C>T (p.Arg51Ter)	Pathogenic
161110	NM_005214.5(CTLA4):c.75del (p.Leu28fs)	Pathogenic
161111	NM_005214.5(CTLA4):c.567+5G>C	Pathogenic
161112	NM_005214.5(CTLA4):c.105C>A (p.Cys35Ter)	Pathogenic
2097298	NM_005214.5(CTLA4):c.216dup (p.Val73fs)	Pathogenic
2128011	NM_005214.5(CTLA4):c.160G>C (p.Ala54Pro)	Pathogenic
2151958	NM_005214.5(CTLA4):c.450T>G (p.Tyr150Ter)	Pathogenic
2151959	NM_005214.5(CTLA4):c.494G>A (p.Trp165Ter)	Pathogenic
2425320	NC_000002.11:g.(?204734049)(204737535_?)del	Pathogenic
2704586	NM_005214.5(CTLA4):c.415T>C (p.Tyr139His)	Pathogenic
3033903	NM_005214.5(CTLA4):c.457+1G>A	Pathogenic
3247378	NC_000002.11:g.(?204730944)(204824322_?)del	Pathogenic
3384671	NM_005214.5(CTLA4):c.346del (p.Ile116fs)	Pathogenic
3722056	NM_005214.5(CTLA4):c.271dup (p.Met91fs)	Pathogenic
3765360	NM_005214.5(CTLA4):c.255_270dup (p.Met91fs)	Pathogenic
4277914	NM_005214.5(CTLA4):c.2T>C (p.Met1Thr)	Pathogenic
4683125	NM_005214.5(CTLA4):c.94_101delinsTTCTCTTCATCA (p.Pro32fs)	Pathogenic
4683126	NM_005214.5(CTLA4):c.361del (p.Ala121fs)	Pathogenic
4718120	NM_005214.5(CTLA4):c.123_124delinsTT (p.Gln42Ter)	Pathogenic
4719495	NM_005214.5(CTLA4):c.174_175del (p.Cys58_Glu59delinsTer)	Pathogenic
4732004	NM_005214.5(CTLA4):c.148_165del (p.Ser50_Ser55del)	Pathogenic
475277	NM_005214.5(CTLA4):c.420C>A (p.Tyr140Ter)	Pathogenic
4819271	NM_005214.5(CTLA4):c.34C>T (p.Gln12Ter)	Pathogenic
4849498	NM_005214.5(CTLA4):c.485del (p.Phe162fs)	Pathogenic
495051	NM_005214.5(CTLA4):c.412C>A (p.Pro138Thr)	Pathogenic
572851	NM_005214.5(CTLA4):c.211del (p.Arg70_Val71insTer)	Pathogenic

SpliceAI

366 predictions. Top by Δscore:

Variant	Effect	Δscore
2:203868049:AAGGT:A	donor_loss	1.0000
2:203868052:G:C	donor_loss	1.0000
2:203871425:GCA:G	donor_gain	1.0000
2:203868052:G:GG	donor_gain	0.9900
2:203868053:T:G	donor_loss	0.9900
2:203870579:A:AG	acceptor_gain	0.9900
2:203870579:AT:A	acceptor_gain	0.9900
2:203870580:T:G	acceptor_gain	0.9900
2:203870580:T:TA	acceptor_gain	0.9900
2:203870584:A:AG	acceptor_gain	0.9900
2:203870585:G:GG	acceptor_gain	0.9900
2:203870585:GCA:G	acceptor_gain	0.9900
2:203870932:TGG:T	donor_loss	0.9900
2:203870934:G:GA	donor_loss	0.9900
2:203870935:T:A	donor_loss	0.9900
2:203870936:GA:G	donor_loss	0.9900
2:203871428:G:GG	donor_gain	0.9900
2:203871440:T:TA	donor_gain	0.9900
2:203872706:A:AG	acceptor_gain	0.9900
2:203872707:G:GG	acceptor_gain	0.9900
2:203870581:GCTA:G	acceptor_loss	0.9800
2:203870582:CTA:C	acceptor_loss	0.9800
2:203870583:TAG:T	acceptor_loss	0.9800
2:203870584:A:C	acceptor_loss	0.9800
2:203870585:G:GT	acceptor_loss	0.9800
2:203870585:GC:G	acceptor_gain	0.9800
2:203870585:GCAAT:G	acceptor_gain	0.9800
2:203870934:G:GG	donor_gain	0.9800
2:203870937:AG:A	donor_loss	0.9800
2:203871372:TTGCA:T	acceptor_loss	0.9800

AlphaMissense

1460 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:203871452:A:C	S178R	0.997
2:203871454:C:A	S178R	0.997
2:203871454:C:G	S178R	0.997
2:203871431:A:C	S171R	0.996
2:203871433:T:A	S171R	0.996
2:203871433:T:G	S171R	0.996
2:203870861:T:C	C129R	0.994
2:203870861:T:A	C129S	0.993
2:203870862:G:C	C129S	0.993
2:203870685:G:C	R70P	0.992
2:203870817:T:C	L114P	0.991
2:203870862:G:A	C129Y	0.991
2:203870855:T:G	Y127D	0.990
2:203870863:C:G	C129W	0.990
2:203870922:T:C	I149T	0.988
2:203870922:T:G	I149S	0.988
2:203870648:T:A	C58S	0.987
2:203870648:T:C	C58R	0.987
2:203870649:G:C	C58S	0.987
2:203872751:T:C	M204T	0.987
2:203870649:G:A	C58Y	0.984
2:203870729:T:C	C85R	0.983
2:203872741:T:C	Y201H	0.982
2:203872783:T:C	F215L	0.982
2:203872785:T:A	F215L	0.982
2:203872785:T:G	F215L	0.982
2:203871437:G:A	G173R	0.981
2:203871437:G:C	G173R	0.981
2:203870637:C:A	A54D	0.980
2:203870729:T:A	C85S	0.978

dbSNP variants (sampled 300 via entrez): RS1000239781 (2:203869652 A>G), RS1000303680 (2:203870228 A>G), RS1000605478 (2:203868453 T>C,G), RS1001038355 (2:203868718 T>C), RS1001673353 (2:203869253 A>G), RS1002187976 (2:203869523 G>A), RS1002640476 (2:203866874 T>A,G), RS1003317903 (2:203873347 T>C,G), RS1003626190 (2:203865771 A>G), RS1004222709 (2:203866951 A>G), RS1005195508 (2:203869040 C>G), RS1005221483 (2:203868712 C>T), RS1005450828 (2:203871042 A>C,G), RS1005834095 (2:203870520 G>A,T), RS1006825232 (2:203870044 A>G)

Disease associations

OMIM: gene MIM:123890 | disease phenotypes: MIM:616100, MIM:615574, MIM:140300, MIM:152700, MIM:601744, MIM:601388, MIM:609755, MIM:607594

GenCC curated gene-disease

Disease	Classification	Inheritance
autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency	Strong	Autosomal dominant
systemic lupus erythematosus	Supportive	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency	Definitive	AD

Mondo (7): autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (MONDO:0014493), congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome (MONDO:0014258), Hashimoto thyroiditis (MONDO:0007699), systemic lupus erythematosus (MONDO:0007915), type 1 diabetes mellitus 12 (MONDO:0011068), celiac disease, susceptibility to, 3 (MONDO:0012341), immunodeficiency, common variable, 1 (MONDO:0011864)

Orphanet (6): Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency (Orphanet:436159), Congenital microcephaly-severe encephalopathy-progressive cerebral atrophy syndrome (Orphanet:391376), Systemic lupus erythematosus (Orphanet:536), OBSOLETE: Common variable immunodeficiency (Orphanet:1572), Late-onset combined immunodeficiency due to ICOS deficiency (Orphanet:695183), NON RARE IN EUROPE: Hashimoto thyroiditis (Orphanet:855)

HPO phenotypes

181 total (30 of 181 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000024	Prostatitis
HP:0000071	Ureteral stenosis
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000099	Glomerulonephritis
HP:0000126	Hydronephrosis
HP:0000155	Oral ulcer
HP:0000163	Abnormal oral cavity morphology
HP:0000246	Sinusitis
HP:0000366	Abnormality of the nose
HP:0000388	Otitis media
HP:0000389	Chronic otitis media
HP:0000407	Sensorineural hearing impairment
HP:0000421	Epistaxis
HP:0000488	Retinopathy
HP:0000491	Keratitis
HP:0000492	Abnormal eyelid morphology
HP:0000505	Visual impairment
HP:0000520	Proptosis
HP:0000579	Nasolacrimal duct obstruction
HP:0000656	Ectropion
HP:0000716	Depression
HP:0000763	Sensory neuropathy
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000864	Abnormality of the hypothalamus-pituitary axis
HP:0000873	Diabetes insipidus
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis

GWAS associations

45 associations (top):

Study	Trait	p-value
GCST000258_7	Type 1 diabetes	8.000000e-11
GCST000392_23	Type 1 diabetes	1.000000e-15
GCST000420_4	Rheumatoid arthritis	6.000000e-09
GCST000612_31	Celiac disease	6.000000e-09
GCST000719_1	Alopecia areata	4.000000e-13
GCST001191_10	Type 1 diabetes	2.000000e-17
GCST001200_2	Graves’ disease	2.000000e-17
GCST001474_16	Hypothyroidism	7.000000e-06
GCST002318_141	Rheumatoid arthritis	3.000000e-25
GCST002318_69	Rheumatoid arthritis	4.000000e-22
GCST002838_1	Myasthenia gravis	9.000000e-11
GCST003043_183	Inflammatory bowel disease	5.000000e-07
GCST003045_68	Ulcerative colitis	1.000000e-07
GCST003988_11	Hypothyroidism	1.000000e-15
GCST004302_16	Primary biliary cholangitis	1.000000e-13
GCST004785_49	Vitiligo	1.000000e-10
GCST004866_12	Alopecia areata	2.000000e-20
GCST005091_1	Subcutaneous adipose tissue	3.000000e-07
GCST005523_12	Celiac disease	1.000000e-15
GCST005531_89	Multiple sclerosis	1.000000e-07
GCST005536_9	Type 1 diabetes	7.000000e-21
GCST005568_31	Rheumatoid arthritis (ACPA-positive)	4.000000e-11
GCST005568_8	Rheumatoid arthritis (ACPA-positive)	4.000000e-08
GCST005569_29	Rheumatoid arthritis	5.000000e-07
GCST005569_35	Rheumatoid arthritis	5.000000e-06
GCST005569_6	Rheumatoid arthritis	7.000000e-11
GCST006048_47	Rheumatoid arthritis (ACPA-positive)	9.000000e-15
GCST006959_129	Rheumatoid arthritis	1.000000e-23
GCST006959_43	Rheumatoid arthritis	9.000000e-20
GCST006979_85	Heel bone mineral density	3.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0009933	Thyroid preparation use measurement
EFO:0010176	keratinocyte carcinoma

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D050031	Hashimoto Disease	C19.874.871.102.500; C20.111.809.500
D008180	Lupus Erythematosus, Systemic	C17.300.480; C20.111.590
C563326	Diabetes Mellitus, Insulin-Dependent, 12 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2364164 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

5 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs231775	Toxicity	3	cyclosporine	Kidney Transplantation
rs231775	Toxicity	3	Antiinflammatory agents;non-steroids
rs3087243	Toxicity	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Psoriasis
rs4553808	Toxicity	3	bortezomib;dexamethasone;melphalan;prednisone
rs4553808	Metabolism/PK	3	tacrolimus	Kidney Transplantation

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs231775	CTLA4	3	2.25	2	Antiinflammatory agents;non-steroids;cyclosporine
rs3087243	CTLA4	3	2.50	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs4553808	CTLA4	3	4.00	2	bortezomib;dexamethasone;melphalan;prednisone;tacrolimus
rs16840252	CTLA4		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — CD molecules

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
lorigerlimab	Binding	10.85	pEC50
cadonilimab	Binding	10.1	pEC50
tremelimumab	Binding	8.91	pKd
quavonlimab	Binding	8.44	pKd
ipilimumab	Binding	8.07	pKd

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation, affects response to substance	3
Arsenic	affects expression, increases expression, affects cotreatment	2
triphenyl phosphate	affects expression	1
trichostatin A	affects cotreatment, increases expression	1
glucuronoxylomannan	increases expression	1
fumonisin B1	increases expression	1
di-n-butylphosphoric acid	affects expression	1
ON 01910	increases expression	1
Indirubin E804	affects cotreatment, decreases expression	1
7-bromoindirubin-3’-oxime	affects cotreatment, decreases expression	1
6,2’,4’-trimethoxyflavone	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Arsenic Trioxide	increases expression	1
Amiodarone	increases expression	1
Benzene	increases expression	1
Hydroxychloroquine	affects cotreatment, decreases expression	1
Methotrexate	affects cotreatment, decreases expression	1
Sulfasalazine	decreases expression, affects cotreatment	1
Valproic Acid	decreases methylation	1
Zearalenone	increases expression	1
Simvastatin	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5256856	Binding	Binding affinity to recombinant human CTLA4 assessed as binding constant at 150 to 200 micromol/L measured for 600 sec bio-layer interferometry assay	Computational design of a cyclic peptide that inhibits the CTLA4 immune checkpoint. — RSC Med Chem

Cellosaurus cell lines

14 cell lines: 6 cancer cell line, 4 transformed cell line, 4 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_6384	CHO-DXB11 CTLA4 Ig-24	Transformed cell line	Female
CVCL_A7ZW	Raji-hCTLA4	Cancer cell line	Male
CVCL_B8E8	Abcam HCT 116 CTLA4 KO	Cancer cell line	Male
CVCL_B8UF	Abcam MCF-7 CTLA4 KO	Cancer cell line	Female
CVCL_B9GG	Abcam A-549 CTLA4 KO	Cancer cell line	Male
CVCL_D7BF	Abeomics CHO-K1 CTLA4	Spontaneously immortalized cell line	Female
CVCL_E6AS	CHO-CTLA4	Spontaneously immortalized cell line	Female
CVCL_E6AT	HEK293-CTLA4	Transformed cell line	Female
CVCL_E6Q4	Genomeditech CHO-K1 H_CTLA4	Spontaneously immortalized cell line	Female
CVCL_E6TU	Genomeditech HEK-293 H_CTLA4	Transformed cell line	Female

Clinical trials (associated diseases)

337 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00120887	PHASE4	COMPLETED	Lupus Atherosclerosis Prevention Study
NCT00125307	PHASE4	COMPLETED	Tacrolimus for the Treatment of Systemic Lupus Erythematosus With Membranous Nephritis
NCT00188188	PHASE4	UNKNOWN	Study of Endothelial Dysfunction in Systemic Lupus and Its Role in Heart Disease
NCT00371501	PHASE4	COMPLETED	Aspirin and Statins for Prevention of Atherosclerosis and Arterial Thromboembolism in Systemic Lupus Erythematosus
NCT00392093	PHASE4	COMPLETED	Effect of Hormone Replacement Therapy on Lupus Activity
NCT00413361	PHASE4	COMPLETED	The Reduction of Systemic Lupus Erythematosus Flares :Study PLUS
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00668330	PHASE4	COMPLETED	Steroid Induced Osteoporosis in Patients With Systemic Lupus Erythematosus
NCT00739050	PHASE4	TERMINATED	Effect of Simvastatin on Endothelial Function in Premenopausal Women With Systemic Lupus Erythematosus (0733-271)(TERMINATED)
NCT00815282	PHASE4	COMPLETED	Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
NCT00828178	PHASE4	COMPLETED	Efficacy of Fish Oil in Lupus Patients
NCT00866229	PHASE4	UNKNOWN	Efficacy and Adverse Effect of Simvastatin Compare to Rosuvastatin in Systemic Lupus Erythematosus (SLE) Patients With Corticosteroid Therapy and High Low-Density Lipoprotein (LDL) Cholesterol Level
NCT00911521	PHASE4	COMPLETED	Immunogenicity and Safety of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Patients With SLE: a Controlled Study
NCT01101802	PHASE4	COMPLETED	Mycophenolate Mofetil in Systemic Lupus Erythematosus (MISSILE)
NCT01112215	PHASE4	COMPLETED	Enteric-coated Mycophenolate Sodium Versus Azathioprine for the Extra-renal Lupus Manifestations
NCT01151644	PHASE4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT01276782	PHASE4	WITHDRAWN	Levothyroxine in Pregnant SLE Patients
NCT01322308	PHASE4	COMPLETED	Effect of Pioglitazone on Endothelial Function in Premenopausal Women With Uncomplicated Systemic Lupus Erythematosus
NCT01359826	PHASE4	WITHDRAWN	The Effect of Milnacipran on Fatigue and Quality of Life in Lupus Patients
NCT01597492	PHASE4	COMPLETED	A Study to Evaluate the Effect of Belimumab on Vaccine Responses in Subjects With Systemic Lupus Erythematosus (SLE)
NCT01632241	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)
NCT01705977	PHASE4	COMPLETED	Belimumab Assessment of Safety in SLE
NCT01753401	PHASE4	COMPLETED	Acthar for the Treatment of Systemic Lupus Erythematosus (SLE) in Patients With a History of Persistently Active Disease
NCT02270970	PHASE4	UNKNOWN	Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy
NCT02477150	PHASE4	COMPLETED	Safety and Immunogenicity of a Zoster Vaccine in SLE
NCT02741960	PHASE4	COMPLETED	The Effect of Metformin on Reducing Lupus Flares
NCT02779153	PHASE4	WITHDRAWN	Acthar SLE (Systemic Lupus Erythematosus)
NCT02953821	PHASE4	COMPLETED	Acthar Gel for Active Systemic Lupus Erythematosus (SLE)
NCT03042260	PHASE4	UNKNOWN	Prophylactic Trimethoprim/Sulfamethoxazole to Prevent Severe Infections in Patients With Lupus Erythematous
NCT03098823	PHASE4	COMPLETED	A Crossover Study to Compare RAYOS to IR Prednisone to Improve Fatigue and Morning Symptoms for SLE
NCT03122431	PHASE4	COMPLETED	Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases
NCT03543839	PHASE4	RECRUITING	Trial of Belimumab in Early Lupus
NCT04447053	PHASE4	UNKNOWN	Sequential Belimumab and T-cell Based Therapy in SLE
NCT04515719	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in SLE Patients
NCT04893161	PHASE4	UNKNOWN	A Model About the Response of Belimumab in SLE
NCT04908865	PHASE4	COMPLETED	Open-label Study of Belimumab Plus Standard Therapy in Chinese Pediatric Participants With Active Systemic Lupus Erythematosus (SLE)
NCT04956484	PHASE4	COMPLETED	Belimumab In Early Systemic Lupus Erythematosus
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