Leukocyte Adhesion Deficiency (LAD) is a defect of cellular adhesion molecules resulting in clinical syndromes. It is a combined (B cell) and cellular (T cell) immunodeficiency disorder.

Leukocyte adhesion deficiency (LAD), is a rare autosomal recessive disorder characterized by immunodeficiency resulting in recurrent infections.[rx] LAD is currently divided into three subtypes: LAD1, LAD2, and the recently described LAD3, also known as LAD-1/variant. In LAD3, the immune defects are supplemented by a Glanzmann thrombasthenia-like bleeding tendency.[rx][rx]

Other Names for This Condition

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

Types of Leukocyte Adhesion Deficiency

Three different types of syndromes have been identified:

  • Leukocyte adhesion deficiency 1: Deficient or defective beta-2 integrin family
  • Leukocyte adhesion deficiency 2: Absent fucosylated carbohydrate ligands for selectins
  • Leukocyte adhesion deficiency 3: Defective activation of all beta integrins (1, 2, and 3)

Type 1 results from mutations in the integrin beta-2 gene (ITGB2), encoding CD18 of beta-2 integrins. Type 2 results from mutations in the glucose diphosphate (GDP)-fucose transporter gene. Type 3 is caused by mutations in the FERMT3 gene (11q13.1), which encodes kindlin-3 in hematopoietic cells.

Pathophysiology

Deficiency of the following integrins: LFA-1/Mac-1, p150 and p95 cause the immunologic and clinical abnormalities seen in leukocyte adhesion deficiency. These proteins functions as adhesion molecules. They are present on lymphocytes, granulocytes, monocytes, and large granular lymphocytes. LFA-1, Mac-1, and glycoprotein 150/95 have a common beta chain but have distinct alpha chains denominated M1 (Mac-1 molecule), L1 (LFA-1 molecule), and X1 (p150,95 molecules). A defect in the beta subunit is accountable for the decreased expression of LFA-1/Mac-1 polypeptide. Natural killer cell activity is not affected. The lesion is on chromosome 21, noted in some patients studied by molecular biology techniques.

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).

Mutations in the ITGB2 gene cause leukocyte adhesion deficiency type 1. This gene provides instructions for making one part (the β2 subunit) of at least four different proteins known as β2 integrins. Integrins that contain the β2 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. β2 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 β2 integrins triggers the transport of the attached leukocyte across the blood vessel wall to the site of infection or injury.

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ITGB2 gene mutations that cause leukocyte adhesion deficiency type 1 lead to the production of a β2 subunit that cannot bind with other subunits to form β2 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

Symptoms of leukocyte adhesion deficiency usually begin in infancy.

  • 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 abnormal inflammatory response and eventually recurrent bacterial infections.
  • Severely affected infants have recurrent or progressive necrotic soft-tissue infections with staphylococcal and gram-negative bacteria, periodontitis, poor wound healing, no pus formation, leukocytosis, and delayed (> 3 weeks) umbilical cord detachment. WBC counts remain high even between infections. Infections become increasingly difficult to control.
  • Less severely affected infants have few serious infections and mild alterations in blood counts.
  • Developmental delay is common in type 2.

Diagnosis of Leukocyte Adhesion Deficiency

Characteristically, 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

Evaluation

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

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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

Treatment of Leukocyte Adhesion Deficiency

  • The treatment of LAD-I is 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 disease.
  • 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 
  • Use of prophylactic immunoglobulin therapy was successful in two patients with a severe form of LAD.
  •   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 foamyviral 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).
  • 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).
The differential diagnosis for neutrophilia includes the following
  • Marrow storage pool shift (inflammation/infection) – Acute neutrophilia from a leukemoid reaction due to the release of neutrophils from the marrow storage pool, due to inflammation and/or infection. Increased numbers of neutrophil bands are usually observed.
  • Pseudoneutrophilia (stress demargination) – Acute temporary neutrophilia as a response caused by a shift of cells from the marginal to the circulating pool, secondary to vigorous exercise or acute physical or emotional stress. Neutrophil counts may be doubled, but lymphocytes and monocytes are generally unaffected by demargination.
  • Myeloproliferative disorder – Juvenile myelomonocytic leukemia can present in infancy with fever, persistent infection, skin and oral bleeding. The leukocyte count is elevated but the differential reveals immature myeloid cells, blasts, and nucleated red cells.
  • Leukocyte adhesion deficiencyn – type II – Leukocyte adhesion deficiency- type II (LAD-II) is similar to LAD-I as it presents with neutrophilia but results from a defect in fucose metabolism causing the absence of Sialyl Lewis X and other fucosylated ligands for the selectins. It is extremely rare and is associated with the Bombay Blood group and mental retardation.
  • Leukocyte adhesion deficiency type III – Leukocyte adhesion deficiency- type III (LAD-III) is similar to LAD-I as it presents with neutrophilia and is due to a defect in integrin activation affecting both neutrophils and platelets. It is extremely rare and is also associated with a bleeding phenotype.
  • Transient myeloproliferative disorder – Leukocytosis with circulating blasts found in infants with Down syndrome or mosaicism for trisomy 21 is associated with GATA-binding factor 1 (GATA1) mutation. Infants often also have hepatosplenomegaly. Median age of presentation is 3 to 7 days with the majority of cases diagnosed prior to age 2 months. Self-resolves by 3 to 6 months in most cases; however, symptomatic infants may require cytarabine.
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The differential diagnosis for delayed umbilical separation includes the following
  • Physiologic umbilical separation – A well infant with delayed separation of the umbilical cord and normal blood counts is extremely unlikely to have LAD-I. The mean time of umbilical cord separation is 13.9 days; however, normal infants are documented to have cord separation from 3 to 45 days.
  • Urachal cyst

References

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