Leukocyte Adhesion Deficiency – Causes, Symptoms, Treatment

Leukocyte adhesion deficiency (LAD) is an immunodeficiency cellular molecules adhesion deficiency type-1 (LAD-I) is a rare, inherited combined deficiency disorder involving both B and T cells and is characterized by an inability of leukocytes to migrate to the site of infection to kill offending microbes. It is a combined (B cell) and cellular (T cell) immunodeficiency disorder. This activity describes the evaluation and management of leukocyte adhesion deficiency and reviews the role of the interprofessional team in improving care for patients with this condition.

Leukocyte adhesion deficiency type 1 is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. Immunodeficiencies are conditions in which the immune system is not able to protect the body effectively from foreign invaders such as viruses, bacteria, and fungi. Starting from birth, people with leukocyte adhesion deficiency type 1 develop serious bacterial and fungal infections.

Other Names for This Condition

  • LAD1
  • leucocyte adhesion deficiency type 1
  • leukocyte adhesion molecule deficiency type 1

Synonyms of Leukocyte Adhesion Deficiency Syndromes

  • LAD syndromes

Subdivisions of Leukocyte Adhesion Deficiency Syndromes

  • congenital disorder of glycosylation type II c
  • LAD I
  • LAD II
  • LAD III
  • leukocyte adhesion deficiency type I
  • leukocyte adhesion deficiency type II
  • leukocyte adhesion deficiency type III
  • Rambon-Hasharon syndrome

Major immunologic features:

  • There is an inability to form pus.
  • There is a deficiency of various glycoproteins including LFA-1/Mac-1, glycoprotein 150/95.
  • Leukocytes cannot migrate to infection sites to kill invading microorganisms due to mutations in the CD18 glycoprotein.
  • Adhesion molecules deficiency results in an abnormal inflammatory response and eventually recurrent bacterial infections.

Causes of Leukocyte Adhesion Deficiency

Primarily, leukocytes cannot escape from the blood to tissues that have been attacked by microbes. Continuous surveillance of foreign antigens by leukocyte trafficking suffers disruption as well. There are three different types of LAD:

  • Type I – in which steady adhesion of leukocyte to endothelial surfaces is defective by mutations in CD18 gene resulting in defective or deficient beta-2 integrin
  • Type II – in which there is an absence of Sialyl Lewis X of E-selectin
  • Type III – in which there is a defect in beta integrins 1, 2, and 3; this impairs the integrin activation cascade – specifically, a mutation in the kindlin-3 gene causes this type of LAD

LAD has an autosomal recessive mode of inheritance.

  • Seven new mutations in the ITGB2 gene reported, which encode the beta2 integrin family including three frameshift deletions (Tyr382fsX9, Asn282fsX41, and Lys636fsX22),¬†two splicing (IVS4-6C>A, IVS7+1G>A) and three missense (Asp128Tyr, Gly716Ala, and Ala239Thr).

Additional cause

Mutations in the¬†ITGB2¬†gene cause leukocyte adhesion deficiency type 1. This gene provides instructions for making one part (the ő≤2 subunit) of at least four different proteins known as ő≤2 integrins. Integrins that contain the ő≤2 subunit are found embedded in the membrane that surrounds¬†white blood cells\¬†(leukocytes). These integrins help leukocytes gather at¬†sites of infection or injury\, where they contribute to the immune response. ő≤2 integrins recognize signs of inflammation and attach (bind) to proteins called ligands on the lining of blood vessels. This binding leads to linkage (adhesion) of the leukocyte to the blood vessel wall. Signaling through the ő≤2 integrins triggers the transport of the attached leukocyte across the blood vessel wall to the site of infection or injury.

ITGB2¬†gene mutations that cause leukocyte adhesion deficiency type 1 lead to the production of a ő≤2 subunit that cannot bind with other subunits to form ő≤2 integrins. Leukocytes that lack these integrins cannot attach to the blood vessel wall or cross the vessel wall to contribute to the immune response. As a result, there is a decreased response to injury and foreign invaders, such as bacteria and fungi, resulting in frequent infections, delayed wound healing, and other signs and symptoms of this condition.

Symptoms of Leukocyte Adhesion Deficiency

The symptoms of LAD syndromes can vary greatly from one person to another based upon the subtype present, the amount of residual protein activity and additional factors. The LAD syndromes are primary immunodeficiency disorders that cause individuals to be abnormally susceptible to developing infections. Affected individuals also have elevated levels of white blood cells (leukocytosis).

LEUKOCYTE ADHESION DEFICIENCY TYPE I
The symptoms of LAD I can vary from one to person to another. Some individuals have a severe form of the disorder that can cause life-threatening complications; other individuals have a milder form. LAD I is usually characterized by recurrent, often severe, bacterial infections, and delayed detachment of the umbilical cord. Fungal infections are also common. Bacterial and fungal infections most often affect the skin and mucous membranes (mucosal surfaces). The absence of pus formation at the site of infection is an important feature that can indicate a leukocyte adhesion deficiency. Delayed detachment of the umbilical cord often occurs along with infection of the umbilical cord stump (omphalitis). Recurrent, bacterial infections usually develop shortly after birth in LAD I and can cause life-threatening complications in many cases. Individuals with the milder form of LAD I have fewer and less severe infections.

After infancy, affected children may develop progressive inflammation of the tissues that surround and support the teeth (periodontitis) and inflammation of the gums (gingivitis). Periodontitis can eventually cause tooth loss. Wounds either from surgery or trauma are slow to heal (delayed wound healing) and may be more likely to scar. Affected individuals may also develop sores in the area surrounding.

LEUKOCYTE ADHESION DEFICIENCY TYPE II
Infants with LAD II develop recurrent, bacterial infections. However, the infections and their complications are usually milder than those seen in infants with LAD I. Pneumonia, chronic middle ear infections (otitis media), infection of the tissues that surround and support the teeth (periodontitis) and localized infection of the tissue underneath the surface of the skin (cellulitis) commonly occur in LAD II. The infections are usually not life-threatening and are often treated in an outpatient basis. No pus formation is seen at the site of infection. Generally, the frequency of infections in LAD II decreases after affected individuals reach three years of age. As affected individuals grow older, severe periodontitis is the main infectious complication.

Unlike LAD I, infants with LAD II do not experience a delay in the separation of the umbilical cord. Individuals with LAD II do have additional complications not seen in LAD I including a unique blood type called the Bombay (hh) blood type. Additional features that characterize LAD II include diminished muscle tone resulting in floppiness (hypotonia), distinctive facial features, severe mental retardation and severe growth deficiencies resulting in short stature.

LAD II may also be known as congenital disorder of glycosylation type IIc due to the primary defect in fucose metabolism.

LEUKOCYTE ADHESION DEFICIENCY TYPE III
Individuals with LAD III have recurrent bacterial and fungal infections that follow a similar course of infection as seen in individuals with LAD I. However, these affected individuals also have a bleeding tendency that can cause life-threatening complications. The bleeding complication of LAD III resembles a rare disorder known as Glanzmann thrombasthenia, which is characterized by impaired function of blood cells required for clotting (platelets). Affected individuals have a tendency to bleed easily and profusely especially after surgical procedures. Other symptoms may include susceptibility to easy bruising, nosebleeds (epistaxis), bleeding from the gums (gingival), and/or large red or purple colored spots on the skin that are caused by bleeding under the skin (subcutaneous). The bleeding problem usually starts at birth.

Individuals who were once classified as having LAD I variant (because of the similar disease expression) are now considered to have LAD III because the underlying genetic cause of LAD III is different from the underlying genetic cause of LAD I.

Diagnosis of Leukocyte Adhesion Deficiency

Typically, diagnosis involves several preliminary tests of immune function, including basic evaluation of the humoral immune system and the cell-mediated immune system. A WBC differential will reveal extremely elevated levels of neutrophils (on the order of 6-10x normal) because they are unable to leave the blood vessels. In the case of LAD-I, a specific diagnosis is done by flow cytometry. This technique will reveal absent or reduced CD18 expression in the leukocyte membrane. Recently, prenatal diagnosis systems have been established, allowing early detection of the disease. LAD-II diagnosis includes the study of different glycosylated forms of the transferrin protein. In LAD-III, as platelet function is also affected, this could be used to differentiate it from the other types

Characteristically, a biopsy of infected tissue demonstrates inflammatory infiltrates completely devoid of neutrophils. Remnants of the umbilical cord can show a loose edematous tissue with remarkably few inflammatory cells. In contrast, there is an elevated level of peripheral blood leucocytes (over 29000/microliters) due to an impaired mobilization of leukocytes to extravascular sites of inflammation.

History and Physical

The classic presentation of leukocyte adhesion deficiency is recurrent bacterial infections, neutrophil adhesion defects, and umbilical cord sloughing delays. The adhesion defects result in poor leukocyte chemotaxis, particularly the neutrophil, with an inability to form pus and neutrophilia.

Individuals with leukocyte adhesion deficiency commonly suffer from bacterial infections beginning in the neonatal period. Infections such as omphalitis, pneumonia, gingivitis, and peritonitis are common and usually life-threatening due to the inability to destroy the invading pathogens. Individuals with LAD do not form abscesses because granulocytes cannot migrate to the sites of infection.

Characteristics of patients with LAD include the following:

LAD I:

  • Delayed separation of the umbilical cord
  • Recurrent pyogenic infections, with onset in the first weeks of life
  • Infections caused meanly by¬†Staphylococcus aureus¬†and¬†Pseudomonas aeruginosa
  • Absent pus formation
  • Periodontitis

LAD II:

  • Recurrent skin infections
  • Pneumonia
  • Bronchiectasis
  • Tuberculosis
  • Denture abnormalities
  • Infections are less severe and fewer as compared to LAD I

LAD III:

  • Omphalitis
  • Osteoporosis like bone features
  • Bleeding complications
  • Hematological abnormalities, e.g., bone marrow failure

Other miscellaneous manifestations may include:

  • Vaginitis
  • Peritonitis
  • Osteomyelitis
  • Perianal abscesses
  • Sinusitis
  • Tracheobronchitis
  • Necrotic soft tissue infections
  • Otitis media
  • Meningitis
  • Graft versus host reaction
  • Recurrent tonsillitis
  • Conjunctivitis
  • Granuloma
  • Oral candidiasis
  • Aphthous stomatitis
  • Urinary tract infections
  • Lymphocytic interstitial pneumonitis
  • Glomerulonephritis
  • Hemolytic-uremic syndrome
  • Nail dystrophy
  • Persistent Hyperinsulinemic hypoglycemia of infancy
  • Pyoderma gangrenosum
  • Megakaryocytic acute myeloid leukemia

The immunological investigation of a patient with leukocyte adhesion deficiency includes:

Flow Cytometry Analysis (definitive test):

  • Demonstrates the absence of¬†functional CD18 and the associated alpha subunit molecules on the surface of leukocytes using CD11 and CD18 monoclonal antibodies (LAD I)
  • Demonstrates the absence of sialyl Lewis X expression (CD15a) using a monoclonal antibody directed against sialyl Lewis X ( LAD-II)

Sequence analysis using genetic testing.

  • To define the exact molecular defect in the beta-2 subunit

Quantitative Serum Immunoglobulins.

  • IgG
  • IgM
  • IgA
  • IgE

Antibody Activity. 

IgG antibodies (post-immunization)

  • Tetanus toxoid
  • Diphtheria toxoid
  • Pneumococcal polysaccharide
  • Polio

IgG antibodies (post-exposure)

  • Rubella
  • Measles
  • Varicella Zoster

Detection of isohemagglutinins (IgM)

  • Anti-type A blood
  • Anti-type B blood

Other assays

  • Test for¬†heterophile antibody
  • Anti-streptolysin O titer
  • Immunodiagnosis of infectious diseases (HIV, hepatitis B, and C, HTLV and dengue)
  • Serum protein electrophoresis

Blood lymphocyte subpopulations

  • Total lymphocyte count
  • T lymphocytes (CD3, CD4, and CD8)
  • B lymphocytes (CD19 and CD20)
  • CD4/CD8 ratio

Lymphocyte stimulation assays

  • Phorbol ester and ionophore
  • Phytohemagglutinin
  • Antiserum to CD3
  • Chemotaxis of human lymphocytes

Phagocytic function

Nitroblue tetrazolium (NBT) test (before and after stimulation with endotoxin)

  • Unstimulated
  • Stimulated

Neutrophil mobility

  • In medium alone
  • In the presence of chemoattractant
  • In vivo and in vitro chemotaxis of granulocytes

Complement System Evaluation

Measurement of individuals components by immunoprecipitation tests, ELISA, or Western blotting

  • C3 serum levels
  • C4 serum levels
  • Factor B serum levels
  • C1 inhibitor serum levels

Hemolytic assays

  • CH50
  • CH100

Complement system functional studies

  • Classical pathway assay (using IgM on a microtiter plate)
  • Alternative pathway assay (using LPS on a microtiter plate)
  • Mannose pathway assay (using mannose on a microtiter plate)

Microbiological studies

  • Nasopharyngeal swab (testing for Rhinovirus)
  • Stool (testing for viral, bacterial or parasitic infection)
  • Sputum (bacterial culture and pneumocystis PCR)
  • Blood (bacterial culture, HIV by PCR, HTLV testing)
  • Urine (testing for cytomegalovirus and proteinuria)
  • Cerebrospinal fluid (culture, chemistry, and histopathology)

Other investigations of immunodeficiency disorders

  • Bone marrow biopsy
  • Complete blood cell count
  • Blood chemistry
  • Histopathological studies
  • Tumoral markers
  • Levels of cytokines
  • Chest x-ray
  • Diagnostic¬†ultrasound
  • Liver function test

Laboratory Testing

  • Initial screening
    • General immunodeficiency screening
      • CBC with differential
      • Comprehensive metabolic profile
      • Quantitative serum immunoglobulins (IgA, IgG, IgM)
      • Lymphocyte subset analyses ‚Äď depending on clinical presentation
    • Rule out other diseases associated with immunodeficiency
      • HIV-1,2¬†testing
      • Plasma cell disorders¬†‚Äď monoclonal protein detection, quantitation, and characterization with serum protein electrophoresis (SPEP), immunofixation electrophoresis (IFE), IgA, IgG, IgM
      • Cystic fibrosis¬†‚Äď sweat chloride testing using an accredited cystic fibrosis center
    • Rule out diseases associated with protein losses (eg, protein-losing enteropathy, nephropathy)
  • More specific screening ‚Äď based on initial screening results
    • Clinical presentation may require multiple immune system investigations (refer to the¬†Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children Testing Algorithm¬†and¬†Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm)
    • Definitive diagnosis, prognostication, genetic counseling, and treatment may require genetic testing
    • Complement testing
  • Flow cytometric analysis
    • Assess the presence of beta 2 (ő≤2) integrins CD11 and CD18
      • Decreased/absent expression of CD11/CD18 ‚Äď consistent with leukocyte adhesion deficiency-1 (LAD1)
        • 2-10% expression ‚Äď moderate deficiency; reasonable survival rate into adulthood
        • >10% expression ‚Äď mild deficiency; may not be recognized until late teen years
        • <2% ‚Äď severe deficiency; majority die in infancy unless bone marrow transplant is performed
      • Normal expression of CD11/CD18 ‚Äď consistent with LAD2 or LAD3
    • Assess the presence of CD15 ‚Äď indicated if LAD2 is suspected
      • Absent expression of CD15 ‚Äď consistent with LAD2
    • Another testing
      • Neutrophil rolling, neutrophil adherence, neutrophil motility ‚Äď performed only in specialized laboratories
      • Bombay blood group phenotype testing ‚Äď present in LAD2
      • Platelet aggregation ‚Äď abnormal in LAD3
      • Molecular sequence analysis ‚Äď defines exact molecular defect

Differential Diagnosis

  • Sepsis
  • Neutropenic disorders
  • Agranulocytosis
  • IRAK-4 deficiency
  • Job syndrome
  • Chronic granulomatous disease
  • Myeloperoxidase deficiency
  • Congenital disorders of glycosylation
  • Leukemoid reaction in infants
  • Other congenital coagulation disorders (particularly in LAD3 due to bleeding tendency)

Treatment of Leukocyte Adhesion Deficiency

  • The treatment of LAD-I is an allogeneic hematopoietic stem cell transplant (HSCT). By the age of 2 years, the disease is fatal in severe cases without HSCT.
  • Ustekinumab, a monoclonal antibody of the p40 subunit common to IL-12 and IL-23, had been used successfully to treat refractory periodontitis and sacral ulcer in a case report with mild LAD I. However, further studies are necessary to determine safety and efficacy, particularly in patients with more severe diseases.
  • Recombinant human interferon-gamma treatment has been used in LAD-I.¬†
  • A trial of fucose supplementation is recommended in all patients diagnosed with LAD II
  • Recombinant factor VIIa is considered effective in treating and preventing severe bleeding in a child patient with LAD III¬†
  • The use of prophylactic immunoglobulin therapy was successful in two patients with a severe form of LAD.
  • More conservative treatment is directed against specific infectious agents. Patients are infected with common pathogenic agents but no with opportunistic ones and should respond well to antimicrobial therapy. The most common pathogens affecting patients with LAD include¬†Proteus,¬†Klebsiella,¬†Staphylococcus aureus, Pseudomonas aeruginosa, and enterococci.¬† Early aggressive treatment should be used or given as prophylactic therapy (e.g., dental procedures).
  • Although patients can receive intensive antibiotherapy and even¬†granulocyte transfusions¬†from healthy donors, the only current curative therapy is the¬†hematopoietic stem cell transplant.[rx]¬†However, progress has been made in¬†gene therapy, an active area of research. Both foamy viral¬†and¬†lentiviral vectors¬†expressing the human¬†ITGB2¬†gene under the control of different promoters have been developed and have been tested so far in preclinical LAD-I models (such as CD18-deficient mice and canine leukocyte adhesion deficiency-affected dogs).

References

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