Diseases of immune dysregulation

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Overview

Classification

Immunodeficiency Affecting Cellular and Humoral Immunity

Combined Immunodeficiency

Predominantly Antibody Deficiency

Diseases of Immune Dysregulation

Congenital Defects of Phagocytes

Defects in Intrinsic and Innate Immunity

Auto-inflammatory Disorders

Complement Deficiencies

Phenocopies of Primary Immunodeficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zahir Ali Shaikh, MD[2], Anmol Pitliya, M.B.B.S. M.D.[3]

Overview

Classification


 
 
Diseases of Immune Dysregulation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(A) Hemophagocytic lymphohistiocytosis (HLH) & EBV susceptibility
 
(B) Syndromes with Autoimmunity and Others
 
 
 
 
 


Hemophagocytic Lymphohistiocytosis (HLH) & EBV Susceptibility


 
 
 
 
 
 
 
 
 
 
Diseases Of Immune Dysregulation:
(A) Hemophagocytic Lymphohistiocytosis (HLH) & EBV Susceptibility
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemophagocytic Lymphohistiocytosis(HLH)
 
 
 
 
 
 
Susceptibility to EBV
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypopigmentation
 
 
Familial Hemophagocytic Lymphohistiocytosis Syndromes
 
 
 
 
 
 
 
EBV Associated with HLH
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chediak Higashi Syndrome:LYST
 
 
Perforin Deficiency(FHL2)
 
 
 
RASGRP1 Deficiency
 
 
XL,XLP1.SH2DIA
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Griscelli Syndrome type2:RAB27a
 
 
UNCBD/Munc13-4 deficiency(FHL3)
 
 
 
CD70 Deficiency
 
 
XL,XLP2,XIAP
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hermansky Pudlak Syndrome type2:AP3B1
 
 
Syntaxin II Deficiency(FHL4)
 
 
 
CTPS1 Deficiency
 
 
AR, CD27 Deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hermansky Pudlak Syndrome type10
 
 
STXBP2/Munc18-2 Deficiency
 
 
 
RLTPR (CARMIL2) Deficiency
 
 
FAAP24 Deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ITK Deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MAGT1 Deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRKCD Deficiency
 
 
 
 
 
 


Syndromes with Autoimmunity and Others


 
 
 
 
 
 
 
 
 
Diseases of Immune Dysregulation:
(B) Syndromes with Autoimmunity and Others
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Syndromes with Autoimmunity
 
 
 
 
 
 
 
Immune Dysregulation with Colitis:
IBD, Normal Tc & Bc
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Increased CD4-CD8-TCR alpha/beta (Double Negative T cells)
 
IL10 Deficiency, IL10, AR
 
IL10Ra Deficiency, IL10RA, AR
 
IL10Rb Deficiency, IL10RB, RA
 
NFATS haploinsufficiency, NAFTS, AD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes
 
Occassionally
 
 
 
 
 
 
NO: Regulatory T cells Defects?
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALPS, Autoimmune Lymphoproliferative Syndrome
 
 
LRBA Deficiency
 
NO
 
 
YES
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALPS-FAS TNFRSF, AD or AR
 
 
STAT3 GOF mutation,STAT3 AD
 
 
 
 
Autoimmune Polyendocrinopathy with candidiasis & ectodermal dystrophy: APECED (APS-1)
 
 
 
IPEX Immune dysregulation, Polyendocrinopathy,enteropathy,X-linked FOXP-3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALPS-FASLG TNFSF6, AR
 
 
 
 
 
 
 
 
ITCH Deficiency, ITCH, AR
 
 
 
CD25 Deficiency, IL2RA, AR
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALPS-Caspase10, Casp10, AD
 
 
 
 
 
 
 
 
ZAP70 combined hylomorphic and activation mutations, ZAP70, AR
 
 
 
CTLA4 deficiency (ALPSV) CTLA4, AD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALPS-Caspase8, Casp8, AR
 
 
 
 
 
 
 
 
Tripeptidyl-peptidase II deficiency, TPP2, AR
 
 
 
BACH2 deficiency. BACH2, AD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FADD deficiency, FADD, AR
 
 
 
 
 
 
 
 
JAK1 GOF, JAK1, AD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prolidase deficiency. PEPD, AR
 
 
 
 
 
 
 
 
 
 


Chediak Higashi Syndrome

Griscelli Syndrome type 2

Hermansky Pudlak Syndrome type 2

  • Hermansky pudlak syndrome type 2 is caused by homozygous or compound heterogenous autosomal recessive mutation in the gene encoding the beta-3A subunit of AP3 complex (AP3B1) on chromosome 5q14.[7]
  • It is characterized by platelet defects, oculocutaneous albinism, immunodeficiency, congenital neutropenia and pulmonary fibrosis.[7]
  • Treatment includes chronic antibiotic therapy and granulocyte colony stimulating factor (G-CSF) because of netropenia and management of complications as they arise.[8]

Hermansky Pudlak Syndrome type 10

  • Hermansky pudlak syndrome type 10 is caused by an autosomal recessive mutation in AP3D1 gene on chromosome 19p13.[9]
  • It is characterized by immunodeficiency, oculocutaneous albinism and severe neurological impairment including severely delayed global development and intractable seizures.[9]
  • Treatment depends upon the manifestations of disease, granulocyte-colony stimulating factor (G-CSF) used when immunodeficiency is present.[10]

Perforin Deficiency

  • Perforin is a glycoprotein responsible for pore formation in cell membranes of target cells. The main source of perforin are natural killer (NK) cells and CD8 positive T cells. A low amount of perforin is also expressed by CD4 positive T cells.[11]

References

  1. M. D. Barbosa, Q. A. Nguyen, V. T. Tchernev, J. A. Ashley, J. C. Detter, S. M. Blaydes, S. J. Brandt, D. Chotai, C. Hodgman, R. C. Solari, M. Lovett & S. F. Kingsmore (1996). "Identification of the homologous beige and Chediak-Higashi syndrome genes". Nature. 382 (6588): 262–265. doi:10.1038/382262a0. PMID 8717042. Unknown parameter |month= ignored (help)
  2. Kaplan, Jerry; De Domenico, Ivana; Ward, Diane McVey (2008). "Chediak-Higashi syndrome". Current Opinion in Hematology. 15 (1): 22–29. doi:10.1097/MOH.0b013e3282f2bcce. ISSN 1065-6251.
  3. M. Eapen, C. A. DeLaat, K. S. Baker, M. S. Cairo, M. J. Cowan, J. Kurtzberg, C. G. Steward, P. A. Veys & A. H. Filipovich (2007). "Hematopoietic cell transplantation for Chediak-Higashi syndrome". Bone marrow transplantation. 39 (7): 411–415. doi:10.1038/sj.bmt.1705600. PMID 17293882. Unknown parameter |month= ignored (help)
  4. Kirtisudha Mishra, Shilpy Singla, Suvasini Sharma, Renu Saxena & Vineeta Vijay Batra (2014). "Griscelli syndrome type 2: a novel mutation in RAB27A gene with different clinical features in 2 siblings: a diagnostic conundrum". Korean journal of pediatrics. 57 (2): 91–95. doi:10.3345/kjp.2014.57.2.91. PMID 24678334. Unknown parameter |month= ignored (help)
  5. I. P. Meschede, T. O. Santos, T. C. Izidoro-Toledo, J. Gurgel-Gianetti & E. M. Espreafico (2008). "Griscelli syndrome-type 2 in twin siblings: case report and update on RAB27A human mutations and gene structure". Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 41 (10): 839–848. PMID 19030707. Unknown parameter |month= ignored (help)
  6. Amira Masri, Faris G. Bakri, Maissa Al-Hussaini, Azmy Al-Hadidy, Rania Hirzallah, Genevieve de Saint Basile & Hanan Hamamy (2008). "Griscelli syndrome type 2: a rare and lethal disorder". Journal of child neurology. 23 (8): 964–967. doi:10.1177/0883073808315409. PMID 18403584. Unknown parameter |month= ignored (help)
  7. 7.0 7.1 Jung, J. (2006). "Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2". Blood. 108 (1): 362–369. doi:10.1182/blood-2005-11-4377. ISSN 0006-4971.
  8. Hengst, Meike; Naehrlich, Lutz; Mahavadi, Poornima; Grosse-Onnebrink, Joerg; Terheggen-Lagro, Suzanne; Skanke, Lars Høsøien; Schuch, Luise A.; Brasch, Frank; Guenther, Andreas; Reu, Simone; Ley-Zaporozhan, Julia; Griese, Matthias (2018). "Hermansky-Pudlak syndrome type 2 manifests with fibrosing lung disease early in childhood". Orphanet Journal of Rare Diseases. 13 (1). doi:10.1186/s13023-018-0780-z. ISSN 1750-1172.
  9. 9.0 9.1 Ammann, S.; Schulz, A.; Krageloh-Mann, I.; Dieckmann, N. M. G.; Niethammer, K.; Fuchs, S.; Eckl, K. M.; Plank, R.; Werner, R.; Altmuller, J.; Thiele, H.; Nurnberg, P.; Bank, J.; Strauss, A.; von Bernuth, H.; zur Stadt, U.; Grieve, S.; Griffiths, G. M.; Lehmberg, K.; Hennies, H. C.; Ehl, S. (2016). "Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome". Blood. 127 (8): 997–1006. doi:10.1182/blood-2015-09-671636. ISSN 0006-4971.
  10. . doi:10.1111/pde.13266. Epub 2017 Oct 16. Check |doi= value (help). Missing or empty |title= (help)
  11. Iwona Osinska, Katarzyna Popko & Urszula Demkow (2014). "Perforin: an important player in immune response". Central-European journal of immunology. 39 (1): 109–115. doi:10.5114/ceji.2014.42135. PMID 26155110.