Pediatric Complement Receptor Deficiency Workup

  • Author: Alan P Knutsen, MD; Chief Editor: Harumi Jyonouchi, MD   more...
 
Updated: Aug 30, 2011
 

Laboratory Studies

  • Extreme neutrophilia (>15,000/mcL) is a constant feature of leukocyte adhesion deficiency (LAD) type 1, type 2, type 3, and Rac2 deficiency because of inability of neutrophil margination.
    • The WBC count is 15-161 X 103/µL (15,000-161,000/mcL) with 50-90% neutrophils.
    • Neutrophilia is present in the absence of infections and increases with infections.
    • In E-selectin deficiency, mild neutropenia is present but increases with infections.
  • The diagnosis of LAD type 1 is confirmed by an absence of CD11a,b,c/CD18 on neutrophils, macrophages, and lymphocytes on flow cytometry.
    • In addition, neutrophil function is impaired, with abnormal adherence, chemotaxis phagocytosis, and deficient respiratory burst.
    • Numbers of T and B cells and their function are normal.
    • However, natural killer (NK)-cell and T-cell cytotoxicity is depressed.
    • Responses on mixed lymphocyte culture (MLC) may be markedly decreased.
    • CD15s expression is normal in LAD type 1.
  • In LAD type 2, CD15s (sLeX) expression is absent on neutrophils. CD11/CD18 expression is normal.
    • Neutrophil rolling is decreased but adhesion is normal.
    • Numbers and function of T and B cells are decreased.
    • Erythrocyte H antigens are absent, leading to expression of the Bombay (hh) phenotype. As a result, anti-H antibodies are present.
  • In examination of infections in children with LAD type 1, signs of inflammation, eg, erythema, pus formation, are decreased to absent.
    • Necrotic cutaneous, mucous membrane, and periodontal infections are the hallmark of LAD type 1.
    • In deep-seated infections, such as in the lungs and abdomen, the same process occurs.
    • Inflammatory infiltrations are decreased.
    • Therefore, findings on chest or abdominal radiography findings may lead to underestimates of the infectious process.
    • Imaging studies more sensitive than radiography, such as chest CT, may define the infectious process better than radiography.
    • Appropriate cultures are obtained from suspected infectious sites. Although inflammatory cells are decreased to absent, microorganisms can be identified.
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Imaging Studies

  • No specific radiographic studies are necessary to make a diagnosis.
  • As previously discussed, imaging studies are useful in diagnosing infections.
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Histologic Findings

  • The most striking finding in biopsies of infections in patients with all forms of LAD is the absence of neutrophils and other inflammatory cells.
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Contributor Information and Disclosures
Author

Alan P Knutsen, MD  Professor of Pediatrics, Director of Pediatric Allergy and Immunology, Director Jeffrey Modell Diagnostic & Research Center for Primary Immuodeficiences (CGCMC), Director of Pediatric Clinical Immunology Laboratory, Department of Pathology, St Louis University Health Sciences Center

Alan P Knutsen, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, and Clinical Immunology Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Ann O'Neill Shigeoka, MD †  Former Clinical Associate Professor, Department of Pediatrics, Division of Immunology-Rheumatology, University of Utah School of Medicine

Ann O'Neill Shigeoka, MD † is a member of the following medical societies: American Federation for Medical Research, Clinical Immunology Society, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

John Wilson Georgitis, MD  Consulting Staff, Lafayette Allergy Services

John Wilson Georgitis, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Chest Physicians, American Lung Association, American Medical Writers Association, and American Thoracic Society

Disclosure: Nothing to disclose.

David Pallares, MD  Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville School of Medicine

David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology

Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD  Associate Professor, Division of Pulmonary, Allergy/Immunology, and Infectious Diseases, Department of Pediatrics, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

References

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Protein defects.
Table 1. Complement Receptors
ReceptorCluster DesignationLigandCell DistributionActivity
CR1CD35C3b/C4bRBC, polymorphonuclear cell, macrophage, B cell, follicular dendritic cellImmune adherence, phagocytosis
CR2CD21C3dg/C3dB cell, follicular dendritic cellCo-receptor for B-cell signaling
CR3CD11b/CD18C3bi, ICAMMyeloidPhagocytosis, immune adherence
CR4CD11c/CD18C3bi, ICAMMyeloidPhagocytosis, immune adherence
C1qRPNoneC1q, MBL, surfactantPolymorphonuclear cell, macrophagePromotes phagocytosis
C3aRNoneC3a, C4aPolymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cellAnaphylatoxin
C4aRNoneC4aPolymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cellAnaphylatoxin
C5aRCD88C5aPolymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cellAnaphylatoxin
ICAM = intercellular adhesion molecule, MBL = mannose-binding lectin
Table 2. Leukocyte Adhesion Defects
DiseaseInheritanceGenetic DefectProtein DefectAffected CellsAffected FunctionManifestations
LAD type 1Autosomal recessiveINTGB2CD18Polymorphonuclear cell, macrophage, lymphocytes, NK cellsTight adherence, chemotaxis, endocytosis, T-cell/NK-cell cytotoxicityDelayed cord separation, skin ulcers, periodontitis, leukocytosis, poor pus formation
LAD type 2Autosomal recessiveFUCT1 encoding for GDP-fucose transporterFucosylated proteins, sialyl-Lewis X (sLeX, CD15s)Polymorphonuclear cell, macrophageRolling, chemotaxis, tetheringSame as LAD type 1 plus hh-blood group, mental retardation
LAD type 3Autosomal recessiveKindlin 3 (FERMT3), involved in activation of integrinKindlin 3Polymorphonuclear cell, macrophage, lymphocytes, NK cellsTight adherenceSame as LAD type 1 plus bleeding tendency
Rac 2 deficiencyPossibly autosomal dominantRAC2Rac2, involved in regulation of actin cytoskeletonPolymorphonuclear cell, decreased TRECsChemotaxis, O2- productionRecurrent infections, poor wound healing, leukocytosis, poor pus formation
E-selectinPossibly autosomal recessiveUnknownE-selectinEndothelial cellsRolling, tetheringRecurrent infections, poor pus formation, mild neutropenia
NK = Natural killer, TRECs = T-cell receptor excision circles
Table 3. Adhesion Molecules
MoleculeCD NumberDistributionLigandFunction
Integrins
LFA-1CD11a/CD18All leukocytesICAM-1, 2, 3Adhesion, migration
CR3CD11b/CD18Polymorphonuclear cell, macrophage, NK cells, eosinophilsICAM-1,2; C3biAdhesion, migration
CR4CD11c/CD18All leukocytesC3bi, ICAM-1, CD23, fibrinogenAdhesion
Alpha4-beta7NoneLymphocytes, NK cells, eosinophilsMadCAM-1, VCAM-1, fibronectinAdhesion, migration, rolling
VLA-4CD49d/CD29Lymphocytes, NK cells, eosinophils, basophilsVCAM-1, fibronectinAdhesion, migration, rolling
Selectins
ECD62EEndothelial cells, plateletsSialylated, fucosylated molecules (sLeX, CD15s) expressed on PSGL-1 and ESL-1Rolling
PCD62PEndothelial cells, plateletsSialylated, fucosylated molecules (sLeX) expressed on PSGL-1No data
LCD62LLeukocytesSialylated, fucosylated molecules (often sulfated) expressed on CD34, MadCAM-1 and other glycoproteins-1Rolling
MadCAM = Mucosal addressin cell adhesion molecule; VCAM = Vascular cell adhesion molecule; VLA = Very late activation antigen
Table 4. Subtypes of Leukocyte Adhesion Deficiency Type 1
SubtypemRNA levelCD18 ExpressionClinical Presentation
1NoneNoneSevere
2LowTraceModerate
3Reference rangeTrace, small protein precursorModerate
4Reference rangeLarge protein precursorSevere
5Reference rangeNormal protein precursorModerate
mRNA = messenger RNA.
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