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X-linked lymphoproliferative disease due to SH2D1A deficiency(XLP1)

MedGen UID:
1770239
Concept ID:
C5399825
Disease or Syndrome
Synonyms: Duncan disease; Duncan's syndrome; EBV infection severe susceptibility to; Epstein Barr virus infection familial fatal; IMMUNODEFICIENCY 5; IMMUNODEFICIENCY, X-LINKED PROGRESSIVE COMBINED VARIABLE; INFECTIOUS MONONUCLEOSIS, SEVERE, SUSCEPTIBILITY TO; Lymphoproliferative syndrome 1, X-linked; Purtilo syndrome; SH2D1A-Related Lymphoproliferative Disease, X-Linked; XLP1
SNOMED CT: X-linked lymphoproliferative syndrome type 1 (1162828001); SH2D1A/SLAM-associated protein deficiency (1162828001); X-linked lymphoproliferative disease due to SH2D1A deficiency (1162828001)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
 
Genes (locations): SH2D1A (Xq25); XIAP (Xq25)
 
Monarch Initiative: MONDO:0024551
OMIM®: 308240
Orphanet: ORPHA538931

Disease characteristics

Excerpted from the GeneReview: X-Linked Lymphoproliferative Disease
X-linked lymphoproliferative disease (XLP) in general is characterized by an inappropriate immune response to Epstein-Barr virus (EBV) infection leading to hemophagocytic lymphohistiocytosis (HLH) or severe mononucleosis, dysgammaglobulinemia, and lymphoproliferative disease (malignant lymphoma). The condition primarily affects males. XLP has two recognizable subtypes, XLP1 (due to pathogenic variants in SH2D1A) and XLP2 (due to pathogenic variants in XIAP). HLH / fulminant infectious mononucleosis is the most common presentation regardless of subtype. HLH is characterized as an acute illness with prolonged and high fever, bi- or trilineage cytopenias, and hepatosplenomegaly, which is often severe or fatal. Death is generally secondary to liver failure or multisystem organ dysfunction. In those with XLP1, dys- or hypogammaglobulinemia can lead to varying degrees of humoral immune dysfunction associated with bronchiectasis and recurrent respiratory infections that, if untreated, may result in death. Lymphoproliferative disease (malignant lymphoma) and other lymphoproliferative diseases are specific to XLP1 and often develop in childhood, usually following EBV exposure. Rarer findings in those with XLP1 can include aplastic anemia, vasculitis, and lymphoid granulomatosis. Males with XLP2 are more likely to have HLH without EBV infection, recurrent episodes of HLH (which is not typically seen in those with XLP1), splenomegaly, and gastrointestinal disease, including enterocolitis and perirectal abscesses or fistulae. Rarely, individuals with XLP2 and inflammatory bowel disease have been reported to develop inflammatory liver disease, which can progress to fatal liver failure. Transient hypogammaglobulinemia has been rarely observed in those with XLP2. To date, neither lymphoproliferative disease nor common variable immunodeficiency has been reported in males with XLP2. Heterozygous females rarely have symptoms. There are, however, increasing numbers of reports of affected females with unfavorable (skewed) X-chromosome inactivation favoring the X chromosome with the pathogenic variant who develop HLH, inflammatory bowel disease, and erythema nodosum. [from GeneReviews]
Authors:
Lauren Meyer  |  Melissa Hines  |  Kejian Zhang, et. al.   view full author information

Additional descriptions

From OMIM
X-linked lymphoproliferative syndrome, or Duncan disease, is a primary immunodeficiency characterized by severe immune dysregulation often after viral infection, typically with Epstein-Barr virus (EBV). It is a complex phenotype manifest as severe or fatal mononucleosis, acquired hypogammaglobulinema, hemophagocytic lymphohistiocytosis (HLH), and/or malignant lymphoma. Other features may include aplastic anemia, red cell aplasia, and lymphomatoid granulomatosis (Purtilo et al., 1977; Purtilo, 1981; Purtilo and Grierson, 1991; Coffey et al., 1998; Booth et al., 2011). Genetic Heterogeneity of X-linked/Autosomal Lymphoproliferative Syndrome See XLP2 (300635), caused by mutation in the XIAP gene (300079), also on Xq25; LPFS1 (613011), caused by mutation in the ITK gene (186973) on chromosome 5q33; LPFS2 (615122), caused by mutation in the CD27 gene (186711) on chromosome 12p13; and LPFS3 (618261), caused by mutation in the CD70 gene (TNFSF7; 602840) on chromosome 19p13.  http://www.omim.org/entry/308240
From MedlinePlus Genetics
X-linked lymphoproliferative disease (XLP) is a disorder of the immune system and blood-forming cells that is found almost exclusively in males. More than half of individuals with this disorder experience an exaggerated immune response to the Epstein-Barr virus (EBV). EBV is a very common virus that eventually infects most humans. In some people it causes infectious mononucleosis (commonly known as "mono"). Normally, after initial infection, EBV remains in certain immune system cells (lymphocytes) called B cells. However, the virus is generally inactive (latent) because it is controlled by other lymphocytes called T cells that specifically target EBV-infected B cells.

XLP can be divided into two types based on its genetic cause and pattern of signs and symptoms: XLP1 (also known as classic XLP) and XLP2. People with XLP2 have not been known to develop lymphoma, are more likely to develop hemophagocytic lymphohistiocytosis without EBV infection, usually have an enlarged spleen (splenomegaly), and may also have inflammation of the large intestine (colitis). Some researchers believe that these individuals should actually be considered to have a similar but separate disorder rather than a type of XLP.

People with XLP may respond to EBV infection by producing abnormally large numbers of T cells, B cells, and other lymphocytes called macrophages. This proliferation of immune cells often causes a life-threatening reaction called hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis causes fever, destroys blood-producing cells in the bone marrow, and damages the liver. The spleen, heart, kidneys, and other organs and tissues may also be affected. In some individuals with XLP, hemophagocytic lymphohistiocytosis or related symptoms may occur without EBV infection.

About one-third of people with XLP experience dysgammaglobulinemia, which means they have abnormal levels of some types of antibodies. Antibodies (also known as immunoglobulins) are proteins that attach to specific foreign particles and germs, marking them for destruction. Individuals with dysgammaglobulinemia are prone to recurrent infections.

Cancers of immune system cells (lymphomas) occur in about one-third of people with XLP.

Without treatment, most people with XLP survive only into childhood. Death usually results from hemophagocytic lymphohistiocytosis.  https://medlineplus.gov/genetics/condition/x-linked-lymphoproliferative-disease

Clinical features

From HPO
Burkitt lymphoma
MedGen UID:
2377
Concept ID:
C0006413
Neoplastic Process
Burkitt lymphoma is a rare, aggressive B-cell lymphoma that accounts for 30 to 50% of lymphomas in children but only 1 to 2% of lymphomas in adults (Harris and Horning, 2006). It results from chromosomal translocations that involve the MYC gene (190080) and either the lambda or the kappa light chain immunoglobulin genes (147220, 147200). Burkitt lymphoma is causally related to the Epstein-Barr virus (EBV), although the pathogenetic mechanisms are not clear.
Lymphoma
MedGen UID:
44223
Concept ID:
C0024299
Neoplastic Process
A cancer originating in lymphocytes and presenting as a solid tumor of lymhpoid cells.
Vasculitis
MedGen UID:
12054
Concept ID:
C0042384
Disease or Syndrome
Inflammation of blood vessel.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Liver failure
MedGen UID:
88444
Concept ID:
C0085605
Disease or Syndrome
A disorder characterized by the inability of the liver to metabolize chemicals in the body. Causes include cirrhosis and drug-induced hepatotoxicity. Signs and symptoms include jaundice and encephalopathy. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic dehydrogenase, and alkaline phosphatase.
Fulminant hepatitis
MedGen UID:
86223
Concept ID:
C0302809
Disease or Syndrome
Acute hepatitis complicated by acute liver failure with hepatic encephalopathy occurring less than 8 weeks after the onset of jaundice.
Hepatic encephalopathy
MedGen UID:
5513
Concept ID:
C0019151
Disease or Syndrome
Central nervous system dysfunction in association with liver failure and characterized clinically (depending on degree of severity) by lethargy, confusion, nystagmus, decorticate posturing, spasticity, and bilateral Babinski reflexes.
Aplastic anemia
MedGen UID:
8063
Concept ID:
C0002874
Disease or Syndrome
Aplastic anemia is a serious disorder of the bone marrow that affects between 2 and 5 persons per million per year. About 75% of these cases are classified as idiopathic (Young, 2000). In about 15% of cases a drug or infection can be identified that precipitates the aplasia, although why only some individuals are susceptible is unclear. In about 5 to 10% of patients, the aplastic anemia is constitutional--i.e., is familial or presents with one or more associated somatic abnormalities (summary by Vulliamy et al., 2002).
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Recurrent pharyngitis
MedGen UID:
488936
Concept ID:
C0747556
Sign or Symptom
An increased susceptibility to pharyngitis as manifested by a history of recurrent pharyngitis.
Recurrent respiratory infections
MedGen UID:
812812
Concept ID:
C3806482
Finding
An increased susceptibility to respiratory infections as manifested by a history of recurrent respiratory infections.
Dysgammaglobulinemia
MedGen UID:
41679
Concept ID:
C0013374
Disease or Syndrome
Selective deficiency of one or more, but not all, classes of immunoglobulins.
Immunodeficiency
MedGen UID:
7034
Concept ID:
C0021051
Disease or Syndrome
Failure of the immune system to protect the body adequately from infection, due to the absence or insufficiency of some component process or substance.
Lymphocytosis
MedGen UID:
9834
Concept ID:
C0024282
Disease or Syndrome
Increase in the number or proportion of lymphocytes in the blood.
Meningitis
MedGen UID:
6298
Concept ID:
C0025289
Disease or Syndrome
Inflammation of the meninges.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Lymphadenopathy
MedGen UID:
96929
Concept ID:
C0497156
Disease or Syndrome
Enlargment (swelling) of a lymph node.
Infectious encephalitis
MedGen UID:
108917
Concept ID:
C0596773
Disease or Syndrome
A disorder of the brain caused by an infectious agent that presents with fever, headache, and an altered level of consciousness. There may also be focal or multifocal neurologic deficits, and focal or generalized seizure activity.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Hemophagocytosis
MedGen UID:
163750
Concept ID:
C0876991
Disease or Syndrome
Phagocytosis by macrophages of erythrocytes, leukocytes, platelets, and their precursors in bone marrow and other tissues.
Reduced natural killer cell activity
MedGen UID:
333452
Concept ID:
C1839969
Finding
Reduced ability of the natural killer cell to function in the adaptive immune response.
Increased circulating IgM level
MedGen UID:
333454
Concept ID:
C1839972
Finding
An abnormally increased level of immunoglobulin M in blood.
Abnormal T cell count
MedGen UID:
866762
Concept ID:
C4021113
Finding
A deviation from the normal count of T cells.
Abnormal B cell count
MedGen UID:
866853
Concept ID:
C4021208
Finding
A deviation from the normal count of B cells, i.e., the cells that are formed in the bone marrow, migrate to the peripheral lymphatic system, and mature into plasma cells or memory cells.
Decreased circulating antibody level
MedGen UID:
892481
Concept ID:
C4048270
Finding
An abnormally decreased level of immunoglobulin in blood.
Severe Epstein Barr virus infection
MedGen UID:
1635633
Concept ID:
C4703482
Disease or Syndrome
An unusually severe Epstein Barr virus (EBV) infection.
Decreased circulating IgG level
MedGen UID:
1720114
Concept ID:
C5234937
Finding
An abnormally decreased level of immunoglobulin G (IgG) in blood.
Hypoalbuminemia
MedGen UID:
68694
Concept ID:
C0239981
Finding
Reduction in the concentration of albumin in the blood.
Recurrent fever
MedGen UID:
811468
Concept ID:
C3714772
Sign or Symptom
Periodic (episodic or recurrent) bouts of fever.
Elevated circulating C-reactive protein concentration
MedGen UID:
892906
Concept ID:
C4023452
Finding
An abnormal elevation of the C-reactive protein level in the blood circulation.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Professional guidelines

PubMed

López-Nevado M, González-Granado LI, Ruiz-García R, Pleguezuelo D, Cabrera-Marante O, Salmón N, Blanco-Lobo P, Domínguez-Pinilla N, Rodríguez-Pena R, Sebastián E, Cruz-Rojo J, Olbrich P, Ruiz-Contreras J, Paz-Artal E, Neth O, Allende LM
Front Immunol 2021;12:671755. Epub 2021 Aug 10 doi: 10.3389/fimmu.2021.671755. PMID: 34447369Free PMC Article
Vince N, Mouillot G, Malphettes M, Limou S, Boutboul D, Guignet A, Bertrand V, Pellet P, Gourraud PA, Debré P, Oksenhendler E, Théodorou I, Fieschi C; DEFI Study Group
Hum Immunol 2018 Jul;79(7):571-577. Epub 2018 Apr 27 doi: 10.1016/j.humimm.2018.04.014. PMID: 29709555
Booth C, Gilmour KC, Veys P, Gennery AR, Slatter MA, Chapel H, Heath PT, Steward CG, Smith O, O'Meara A, Kerrigan H, Mahlaoui N, Cavazzana-Calvo M, Fischer A, Moshous D, Blanche S, Pachlopnik Schmid J, Latour S, de Saint-Basile G, Albert M, Notheis G, Rieber N, Strahm B, Ritterbusch H, Lankester A, Hartwig NG, Meyts I, Plebani A, Soresina A, Finocchi A, Pignata C, Cirillo E, Bonanomi S, Peters C, Kalwak K, Pasic S, Sedlacek P, Jazbec J, Kanegane H, Nichols KE, Hanson IC, Kapoor N, Haddad E, Cowan M, Choo S, Smart J, Arkwright PD, Gaspar HB
Blood 2011 Jan 6;117(1):53-62. Epub 2010 Oct 6 doi: 10.1182/blood-2010-06-284935. PMID: 20926771Free PMC Article

Recent clinical studies

Etiology

Sacco KA, Notarangelo LD, Delmonte OM
Clin Microbiol Infect 2023 Apr;29(4):457-462. Epub 2022 Oct 6 doi: 10.1016/j.cmi.2022.10.003. PMID: 36209991Free PMC Article
López-Nevado M, González-Granado LI, Ruiz-García R, Pleguezuelo D, Cabrera-Marante O, Salmón N, Blanco-Lobo P, Domínguez-Pinilla N, Rodríguez-Pena R, Sebastián E, Cruz-Rojo J, Olbrich P, Ruiz-Contreras J, Paz-Artal E, Neth O, Allende LM
Front Immunol 2021;12:671755. Epub 2021 Aug 10 doi: 10.3389/fimmu.2021.671755. PMID: 34447369Free PMC Article
Xu T, Zhao Q, Li W, Chen X, Xue X, Chen Z, Du X, Bai X, Zhao Q, Zhou L, Tang X, Yang X, Kanegane H, Zhao X
Eur J Pediatr 2020 Feb;179(2):327-338. Epub 2019 Nov 21 doi: 10.1007/s00431-019-03512-7. PMID: 31754776Free PMC Article
Latour S, Winter S
Front Immunol 2018;9:1103. Epub 2018 Jun 4 doi: 10.3389/fimmu.2018.01103. PMID: 29942301Free PMC Article
Marsh RA, Madden L, Kitchen BJ, Mody R, McClimon B, Jordan MB, Bleesing JJ, Zhang K, Filipovich AH
Blood 2010 Aug 19;116(7):1079-82. Epub 2010 May 20 doi: 10.1182/blood-2010-01-256099. PMID: 20489057Free PMC Article

Diagnosis

López-Nevado M, González-Granado LI, Ruiz-García R, Pleguezuelo D, Cabrera-Marante O, Salmón N, Blanco-Lobo P, Domínguez-Pinilla N, Rodríguez-Pena R, Sebastián E, Cruz-Rojo J, Olbrich P, Ruiz-Contreras J, Paz-Artal E, Neth O, Allende LM
Front Immunol 2021;12:671755. Epub 2021 Aug 10 doi: 10.3389/fimmu.2021.671755. PMID: 34447369Free PMC Article
Velnati S, Centonze S, Girivetto F, Baldanzi G
Int J Mol Sci 2021 May 29;22(11) doi: 10.3390/ijms22115816. PMID: 34072296Free PMC Article
Canna SW, Marsh RA
Blood 2020 Apr 16;135(16):1332-1343. doi: 10.1182/blood.2019000936. PMID: 32107531Free PMC Article
Xu T, Zhao Q, Li W, Chen X, Xue X, Chen Z, Du X, Bai X, Zhao Q, Zhou L, Tang X, Yang X, Kanegane H, Zhao X
Eur J Pediatr 2020 Feb;179(2):327-338. Epub 2019 Nov 21 doi: 10.1007/s00431-019-03512-7. PMID: 31754776Free PMC Article
Filipovich AH, Zhang K, Snow AL, Marsh RA
Blood 2010 Nov 4;116(18):3398-408. Epub 2010 Jul 26 doi: 10.1182/blood-2010-03-275909. PMID: 20660790Free PMC Article

Therapy

Ruffo E, Malacarne V, Larsen SE, Das R, Patrussi L, Wülfing C, Biskup C, Kapnick SM, Verbist K, Tedrick P, Schwartzberg PL, Baldari CT, Rubio I, Nichols KE, Snow AL, Baldanzi G, Graziani A
Sci Transl Med 2016 Jan 13;8(321):321ra7. doi: 10.1126/scitranslmed.aad1565. PMID: 26764158Free PMC Article
Marsh RA, Bleesing JJ, Chandrakasan S, Jordan MB, Davies SM, Filipovich AH
Biol Blood Marrow Transplant 2014 Oct;20(10):1641-5. Epub 2014 Jun 9 doi: 10.1016/j.bbmt.2014.06.003. PMID: 24923536
Coraglia A, Felippo M, Schierloh P, Malbran A, de Bracco MM
Clin Immunol 2011 Dec;141(3):357-64. Epub 2011 Sep 22 doi: 10.1016/j.clim.2011.09.007. PMID: 21996454
Booth C, Gilmour KC, Veys P, Gennery AR, Slatter MA, Chapel H, Heath PT, Steward CG, Smith O, O'Meara A, Kerrigan H, Mahlaoui N, Cavazzana-Calvo M, Fischer A, Moshous D, Blanche S, Pachlopnik Schmid J, Latour S, de Saint-Basile G, Albert M, Notheis G, Rieber N, Strahm B, Ritterbusch H, Lankester A, Hartwig NG, Meyts I, Plebani A, Soresina A, Finocchi A, Pignata C, Cirillo E, Bonanomi S, Peters C, Kalwak K, Pasic S, Sedlacek P, Jazbec J, Kanegane H, Nichols KE, Hanson IC, Kapoor N, Haddad E, Cowan M, Choo S, Smart J, Arkwright PD, Gaspar HB
Blood 2011 Jan 6;117(1):53-62. Epub 2010 Oct 6 doi: 10.1182/blood-2010-06-284935. PMID: 20926771Free PMC Article
Woon ST, Ameratunga R, Croxson M, Taylor G, Neas K, Edkins E, Browett P, Gane E, Munn S
Scand J Immunol 2008 Aug;68(2):153-8. doi: 10.1111/j.1365-3083.2008.02128.x. PMID: 18702745

Prognosis

Sacco KA, Notarangelo LD, Delmonte OM
Clin Microbiol Infect 2023 Apr;29(4):457-462. Epub 2022 Oct 6 doi: 10.1016/j.cmi.2022.10.003. PMID: 36209991Free PMC Article
López-Nevado M, González-Granado LI, Ruiz-García R, Pleguezuelo D, Cabrera-Marante O, Salmón N, Blanco-Lobo P, Domínguez-Pinilla N, Rodríguez-Pena R, Sebastián E, Cruz-Rojo J, Olbrich P, Ruiz-Contreras J, Paz-Artal E, Neth O, Allende LM
Front Immunol 2021;12:671755. Epub 2021 Aug 10 doi: 10.3389/fimmu.2021.671755. PMID: 34447369Free PMC Article
Xu T, Zhao Q, Li W, Chen X, Xue X, Chen Z, Du X, Bai X, Zhao Q, Zhou L, Tang X, Yang X, Kanegane H, Zhao X
Eur J Pediatr 2020 Feb;179(2):327-338. Epub 2019 Nov 21 doi: 10.1007/s00431-019-03512-7. PMID: 31754776Free PMC Article
Booth C, Gilmour KC, Veys P, Gennery AR, Slatter MA, Chapel H, Heath PT, Steward CG, Smith O, O'Meara A, Kerrigan H, Mahlaoui N, Cavazzana-Calvo M, Fischer A, Moshous D, Blanche S, Pachlopnik Schmid J, Latour S, de Saint-Basile G, Albert M, Notheis G, Rieber N, Strahm B, Ritterbusch H, Lankester A, Hartwig NG, Meyts I, Plebani A, Soresina A, Finocchi A, Pignata C, Cirillo E, Bonanomi S, Peters C, Kalwak K, Pasic S, Sedlacek P, Jazbec J, Kanegane H, Nichols KE, Hanson IC, Kapoor N, Haddad E, Cowan M, Choo S, Smart J, Arkwright PD, Gaspar HB
Blood 2011 Jan 6;117(1):53-62. Epub 2010 Oct 6 doi: 10.1182/blood-2010-06-284935. PMID: 20926771Free PMC Article
Schuster V, Kreth HW
Immunol Rev 2000 Dec;178:21-8. doi: 10.1034/j.1600-065x.2000.17819.x. PMID: 11213803

Clinical prediction guides

Khanolkar A, Wilks JD, Liu G, Caparelli EA, De Moura M, Yap KL, Mustafa A, Kadri S, Huang W, Zheng XT
Immunohorizons 2020 Apr 10;4(4):153-164. doi: 10.4049/immunohorizons.1900060. PMID: 32276922
Xu T, Zhao Q, Li W, Chen X, Xue X, Chen Z, Du X, Bai X, Zhao Q, Zhou L, Tang X, Yang X, Kanegane H, Zhao X
Eur J Pediatr 2020 Feb;179(2):327-338. Epub 2019 Nov 21 doi: 10.1007/s00431-019-03512-7. PMID: 31754776Free PMC Article
Gifford CE, Weingartner E, Villanueva J, Johnson J, Zhang K, Filipovich AH, Bleesing JJ, Marsh RA
Cytometry B Clin Cytom 2014 Jul;86(4):263-71. Epub 2014 Feb 19 doi: 10.1002/cyto.b.21166. PMID: 24616127
Bassiri H, Janice Yeo WC, Rothman J, Koretzky GA, Nichols KE
Immunol Res 2008;42(1-3):145-59. doi: 10.1007/s12026-008-8048-7. PMID: 18815745
Benoit L, Wang X, Pabst HF, Dutz J, Tan R
J Immunol 2000 Oct 1;165(7):3549-53. doi: 10.4049/jimmunol.165.7.3549. PMID: 11034354

Recent systematic reviews

López-Nevado M, González-Granado LI, Ruiz-García R, Pleguezuelo D, Cabrera-Marante O, Salmón N, Blanco-Lobo P, Domínguez-Pinilla N, Rodríguez-Pena R, Sebastián E, Cruz-Rojo J, Olbrich P, Ruiz-Contreras J, Paz-Artal E, Neth O, Allende LM
Front Immunol 2021;12:671755. Epub 2021 Aug 10 doi: 10.3389/fimmu.2021.671755. PMID: 34447369Free PMC Article

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