Sandbox:Zahir

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

Algorithm

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

Pathophysiology

Pathology

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Diseases		A	B
ABC	Type 1
	Type 2
DEF

Algorithm

Combined Immunodeficiencies Generally Less Pronounced than Severe Combined Immunodeficiency

Low CD4: MHC II Expression?

Low CD8

Low B Cells

Ig: Often Normal

Ig Low

Normal Ig but Low Specific Antibody Response

Absent: MHCII Deficiency

Present: XL: MAGT 1 Def:, AR: LCK Def:, AD: UNC119 Def:

IL2IR Def:

MALT1 Def:

CD8 def:

ZAP70 def:

MHC1 def:

DOCK8 def:

MST1 def:

IL21 def:

NIK def:

Moesin def:

CD3Y def:

RHOH def:

TCR alpha def:

BCL11B def:

OX40 def:

LAT def

DOCK2 def:

CARDII def:(LOF)

BCL10 def:

IKBKB Def:

ICOS def:

TFRC def:

RelB def:

CD40 ligand def:(CD154)

Algorithm

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

Yes

Occassionally

NO: Regulatory T cells Defects?

IL10Ra Deficiency, IL10RA, AR

ALPS, Autoimmune Lymphoproliferative Syndrome

LRBA Deficiency

NO

YES

IL10Rb Deficiency, IL10RB, RA

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

NFATS haploinsufficiency, NAFTS, AD

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

Algorithm

Defects in Intrinsic & Innate Immunity: (A) Bacterial and Parasitic Infections

Predisposition to Invasive Bacterial Infections (pyrogens)

Predisposition to Parasitic & Fungal Infections

Others

IRAK4 Deficiency, IRAK4, AR, MyD88 Deficiency, MYD88, AR

Osteopetrosis

IRAK-1 Deficiency:IRAK1,XL

Predisposition to mucocutaneous candidiasis(CMC)

CARD9 Deficiency, CARD9, AR

Hyderadenitis Suppurativa

TIRAP Deficiency, TIRAP, AR

STAT1 GOF, STAT1, AD

Trypanosomiasis APOL1, AD

Acute liver failure due to NBAS deficiency, NBAS, AR

Isolated Congenital Asplenia, RPSA, AD; HMOX, AR

IL-17F Deficiency, IL-17F, AD

Acute necrotizing encephalopathy, RANBP2, AD

IL-17RA Deficiency, IL-17RA, AR

IL-17RC Deficiency, IL-17RC, AR

ACT1 Deficiency, ACT1, AR

Algorithm

Defects in Intrinsic & Innate Immunity: (B) MSMD & Viral Infections

Mendelian susceptibility to mycobacterial disease(MSMD)

Predominant susceptibility to viral infections

Severe Phenotypes

Moderate Phenotypes

Epidermodysplasia verruciformis(HPV)

Predisposition to severe viral infections

Herpes simplex encephalitis

Complete IFNGR1 def: and IFNGR2 def:, IFNGR1,IFNGR2,AR

IL12 & 23 receptor B1 chain def:, IL12P40 def:, STAT1 LOF, Partial IFNYR1 & 2, AD IFNGR1, TyK2 def:

EVER1 def:, TMC6, AR

STAT1 def: (AR LOF)

ISG15 def:, ISG15,AR; Macrophage Gp91 Phox def:CYBB,XL,IRG8 def:,IRF8,AD; IRF8 def:, IRF8 AR; RORc def:, ROCR,AR; JACK1(LOF),JAK1,AR

EVER2 def:, TMC8,AR

STAT2 def: (STAT2 AR)

WHIM (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) Syndrome, CXCR4, AD,GOF

IRF7 def: (IRF7,AR)

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CD16 def: (FCGR3A,AR)

MDAS def: (LOF), IFIH1,AR

Algorithm

Complement Deficiencies

Susceptibility to Infections

HIGH

LOW

Disseminated Nisserial Infections

Recurrent Pyogenic Infections

SLE like syndrome

Atypical hemolytic uremic syndrome

Others

Absent CH50 & AH50 hemolytic activity, defective bacterial activity

Normal CH50, Absent AH50 hemolytic activity

C3LOF,C3,AR

C1q def: C1QA, C1QB, C1QC

C3GOF, C3, AD

C1 inhibitor SERPING1, AD

C5 def:,C5

Properdin def:, PFC, XL

MASP2 def:, MASP2, AR

C1r def:

FactorB, GOF, CFB, AD

Membrane attack complex inhibitor def:, CD59

C6 def:, C6

Factor D def:, CFD, AR

Fincolin3 def:, FCN3, AR

C1s def:

Factor H def:, CFH, AD or AR

CD55 def:, (CHAPLE disease), AR

C7 def:, C7+vasculitis

Factor B, CFB, LOF, AR

C2 def:

Factor H related protein def:, CFHR1-5, AR, AD

C8 def:, C8A, C8B, C8G

C4 def:, C4A, C4B, AR

Factor I def:, AR

C9 def:, C9 mild susceptibility

Thrombomodulin def:, THBD, AD

Membrane cofactor protein def:, CD46, AD