Find information on thousands of medical conditions and prescription drugs.

Leukocyte adhesion deficiency syndrome

Leukocyte adhesion deficiency, abbreviated LAD, is a rare autosomal recessive disorder characterized by immunodeficiency resulting in recurrent infections. The disorder is often divided into two separate genotypes called type I and type II, with type II being associated with fewer infections but more developmental delay. more...

Amyotrophic lateral...
Bardet-Biedl syndrome
Lafora disease
Landau-Kleffner syndrome
Langer-Giedion syndrome
Laryngeal papillomatosis
Lassa fever
LCHAD deficiency
Leber optic atrophy
Ledderhose disease
Legg-Calvé-Perthes syndrome
Legionnaire's disease
Lemierre's syndrome
Lennox-Gastaut syndrome
Lesch-Nyhan syndrome
Leukocyte adhesion...
Li-Fraumeni syndrome
Lichen planus
Limb-girdle muscular...
Lipoid congenital adrenal...
Lissencephaly syndrome...
Liver cirrhosis
Lobster hand
Locked-In syndrome
Long QT Syndrome
Long QT syndrome type 1
Long QT syndrome type 2
Long QT syndrome type 3
Lung cancer
Lupus erythematosus
Lyell's syndrome
Lyme disease
Lysinuric protein...


LAD is a rare disease; its estimated prevalence is 1 in 100,000 births. There is no described racial or ethnic predilection.

Clinical manifestations

LAD was first recognized as a distinct clinical entity in the 1970s. The classic descriptions of LAD included recurrent bacterial infections, defects in neutrophil adhesion, and a delay in umbilical cord sloughing. The defects in adhesion result in poor neutrophil chemotaxis and phagocytosis.

Patients with LAD suffer from bacterial infections beginning in the neonatal period. Infections such as omphalitis, pneumonia, gingivitis, abcesses, and peritonitis are common and often life-threatening due to the infant's inability to properly destroy the invading pathogens.

Molecular defect

The inherited molecular defect in patients with LAD is a deficiency of the beta-2 integrin subunit of the leukocyte cell adhesion molecule, which is found on chromosome 21. This subunit is involved in making three other proteins (LFA-1, CR3, and Mac-1) This basically means that a gene which creates a protein does not function properly. This results in the lack of important molecules which help neutrophils make their way from the blood stream into the infected areas of the body (ie the lungs in pneumonia). Those neutrophils which do manage to make it to the infected areas have a difficult time "swallowing" the bacteria leading to infection (this is known as impaired phagocytosis). Therefore, the infection is allowed to spread unimpeded and cause serious injury to important tissue.


Typically diagnosis is made after several preliminary tests of immune function are made, including basic evaluation of the humoral immune system and the cell-mediated immune system. Specific diagnosis is made through monoclonal antibody testing for CR3, one of the three complete proteins which fail to form properly as a result of beta-2 integrin subunit deficiency.


Once the diagnosis of LAD is made, bone marrow transplantation is the current standard of care. However, some progress has been made in gene therapy, an active area of research.


[List your site here Free!]

Malnutrition impairs CD11b/CD18 expression on circulating polymorphonuclear neutrophils and subsequent exudation into inflammatory sites in the early phase
From JPEN: Journal of Parenteral and Enteral Nutrition, 9/1/00 by Ikeda, Shigeo

ABSTRACT. Background: The effects of malnutrition on polymorphonuclear neutrophil (PMN) exudation are not well understood. The purpose of this study was to examine the effects of short-term dietary restriction on adhesion molecule expression on circulating PMNs and PMN exudation into the inflamed site in a glycogen-induced peritonitis model. Methods: Twelve mice were randomly assigned to one of two groups. The ad libitum and diet-restricted groups received mouse chow ad libitum (estimated consumption: 132 g/kg per day) and 33 g/kg per day, respectively, for 7 days. Then, 2 mL of a 1% glycogen solution was intraperitoneally administered to all mice. After 4 hours, the animals were killed. Whole blood was drawn by cardiac puncture. Peritoneal exudative cells were harvested by lavaging the peritoneal cavity. Expressions of CDllb, CD 18, and CD62L were measured by flow cytometry. Results: Dietary restriction did not affect the numbers of circulating leukocytes, PMNs, or monocytes. However, CD llb and CD18 expressions on circulating PMNs were significantly lower in the diet-restricted than in the ad libitum group. In contrast, CD62L expression on circulating PMNs was not affected by dietary restriction. The number of exudative PMNs was significantly lower in the diet-restricted group than in the ad libitum group. The expressions of CDllb, CD18 and CD62L on exudative PMNs were unaffected by dietary restriction. There was a significant positive correlation between exudative PMN numbers and CD18 expression on circulating PMNs. Conclusions: Severe dietary restriction in our murine model decreased [32 integrin expression on circulating PMNs and inhibited PMN exudation into inflamed sites in the early phase of inflammation. These events may increase susceptibility to bacterial infection. Nutritional replenishment may improve host defense in part by enhancing PMN adhesion molecule expression. (Journal of Parenteral and Enteral Nutrition 24:276-279, 2000)

Previous studies have demonstrated that malnutrition leads to impaired host defense, resulting in an increased susceptibility to infection.1,2 Polymorphonuclear neutrophils (PMNs) play pivotal roles in the host response to microbial infection. However, the reported effects of malnutrition on PMN function are contradictory. Some investigators have demonstrated that malnutrition impairs chemotaxis and phagocytosis by PMNs,3,4 while other studies have failed to show any substantial effects of malnutrition on PMN functions.5 Moreover, investigations concerning the adverse effects of malnutrition on PMNs are based primarily on circulating PMNs.5 However, exudative PMNs play important roles in host defense at the local site. Interaction with endothelial cells is fundamental to the localized exudation of PMNs into extravascular inflammatory sites.6 Recent studies have revealed that adhesion molecules on both PMNs and endothelial cells contribute to this interaction.7,8 However, few studies have investigated the effects of malnutrition on PMN exudation. Moreover, there are no reports on the effects of malnutrition on adhesion molecule expression on PMNs. We examined the effects of short term dietary restriction on adhesion molecule expression on circulating PMNs, and PMN exudation into inflamed sites, in the early phase of glycogen-induced peritonitis in a murine model.


Specific pathogen-free 8-week-old male C57BL/6J mice (Japan SLC, Hamamatsu, Japan) were used for the experiments. The mice were kept in animal facilities for 1 week before experiment initiation to allow acclimation. They were exposed to constant temperature (24C) and humidity (60%) and were fed standard mouse chow (Oriental Koubo, Tokyo, Japan). Regular mouse chow contains protein, fat, carbohydrate, cellulose, minerals, and a vitamin mix (24.6, 5.6, 6.4, 3.1, 3.5, and 0.4 g per 100 g of diet, respectively). All studies were performed in accordance with the Guide for Animal Experimentation, Faculty of Medicine, University of Tokyo. Our institutional review board approved the experimental protocol.


Twelve 8-week-old male C57BL/6J mice were randomly assigned into one of two groups. The ad libitum and diet-restricted groups received regular mouse chow ad libitum and 33 g/kg per day (120 kcal/kg per day), respectively, for 7 days. Our preliminary experiment revealed that the average chow consumption by mice with free access to chow was 132 g/kg per day, which is equivalent to 480 kcal/kg per day. Then, 2 ml of a 1% glycogen solution (Sigma, St. Louis, MO, USA), which elicits cell exudation, was intraperitoneally administered to all mice. After 4 hours, the animals were killed. A heparinized whole-blood sample was obtained by cardiac puncture. Each 50-(mu)L whole-blood sample was used for counting the number of leukocytes by hemocytometer (Celltac, MEK-6258; Nihon Kouden, Tokyo, Japan). Whole-blood samples were centrifuged at 400g for 5 minutes to remove plasma and then stored in 1-mL quantities with RPMI-1640 (Nikken Biomedical Laboratory, Kyoto, Japan) supplemented with 1% fetal calf serum (FCS) at 4C until sample measurement. Peritoneal exudative cells (PECs) were harvested by lavaging the peritoneal cavity with 5 mL of phosphate-buffered saline (PBS; Nikken Biomedical Laboratory) without Ca^sup 2+^ or Mg^sup 2+^. Before harvesting the peritoneal lavage fluid, the abdominal wall was gently rubbed three times. Contaminating erythrocytes were lysed with distilled water. PECs were then resuspended in RPMI-1640 supplemented with 1% FCS. Live PECs were counted by trypan blue exclusion and adjusted to 1 X 10^sup 6^/mL.


The monoclonal antibodies (mAb) used were R-phycoerythrin (R-PE)-conjugated rat antimouse CD11b (integrin alpha^sub M^beta^sub 2^ chain), fluorescein isothiocyanate (FITC)-conjugated rat antimouse CD18 (integrin Beta^sub 2^ chain), and CD62L mAbs (r.-selectin) (Pharmingen, San Diego, CA). One hundred microliters of the PEC suspension and washed whole-blood samples were incubated with saturating amounts of anti-CDllb, anti-CD18, anti-CD62L mAbs, or the related isotype antibodies for 30 minutes at 4degC. At the end of incubation, the cells were washed twice with cold PBS followed by fixation with 0.5 mL of 1% paraformaldehyde.


The flow cytometric analysis was performed using FACScan (Becton Dickinson Immunocytometry Systems, San Jose, CA). In each PEC sample, 10,000 leukocytes, and in whole blood samples, 20,000 leukocytes were counted. PMNs and monocytes/macrophages were gated using morphologic characteristics displayed on a dot plot of forward light scatter Us side scatter. The results of adhesion molecule expression on PMNs and macrophages are expressed as mean channel fluorescence intensity.


Cytocentrifuged cells were fixed in methanol. Then, using the Wright-Giemsa staining technique (Muto Pure Chemicals, Tokyo, Japan), the percentages of PMNs, macrophages, and lymphocytes in both circulating leukocytes and PECs were determined by light microscopy at 40OX magnification. Sample identity was blinded before counting. Two hundred cells per slide were examined.


Data are presented as means +/- SE. To achieve a normal distribution, levels of PEC, exudated PMN, and macrophage numbers were transformed, if necessary, to a logarithmic scale before statistical analysis. Statistical analyses were done using the unpaired t test. Linear regression analysis was also performed. Differences were defined as statistically significant when the p value was


Body Weight Change

Percent body weight (BW at sacrifice/predietary restriction) was significantly lower in the diet-restricted than in the ud libitum group (73 +/- 2 and 107% +/-1%, respectively, p

Changes in Total and Differential Counts of Circulating and Exudative Cells

Dietary restriction did not affect the numbers of circulating leukocytes, PMNs, monocytes, or lymphocytes (Table I). However, after 4 hours of intraperitoneal glycogen injection, the total PEC number was significantly lower in the diet-restricted than in the ad libitum group (Fig. 1). Moreover, the numbers of exudative PMNs and macrophages were significantly lower in the diet-restricted than in the ad libitum group.

Adhesion Molecule Expression on Circulating and Exudative Phagocytes

CD11b and CD18 expressions on circulating PMNs were both significantly lower in the diet-restricted group than in the ad libitum group (Table II). In contrast, CD62L expression on circulating PMNs was not affected by dietary restriction. CD11b and CD18 expressions on peritoneal exudative PMNs were higher than those on circulating PMNs in both groups. On the contrary, CD62L expression was lower on peritoneal exudative PMNs than on circulating PMNs in both groups. Expressions of CDllb, CD18, and CD62L on exudative PMNs were unaffected by dietary restriction. There was a significant positive correlation between exudative PMN numbers and CD18 expression on circulating PMNs (r = .73, p

CD18 expression on circulating monocytes was also significantly lower in the diet-restricted than in the ad libitum group (Table II). CDllb and CD62L expressions on circulating monocytes were lower in the dietrestricted than in the ad libitum group, but the difference was not significant. There was a significant positive correlation between the number of exudative macrophages and CD18 expression on circulating monocytes (r = .68, p


Exudative leukocytes, particularly PMNs, serve to eliminate pathogens in the peritoneal cavity during peritonitis. Expression of adhesion molecules, such as CDllb, CD18, and CD62L on leukocytes regulates leukocyte-endothelial interaction, resulting in leukocyte exudation.6 In patients with leukocyte adhesion deficiency-1 syndrome, which is characterized by a deficiency of Beta2 integrin molecules, there is impaired migration of PMNs, resulting in recurrent bacterial infection.9 Clinically, patients with malnutrition are more susceptible to infection than well-nourished patients.1,2 Therefore, we hypothesized that malnutrition may cause deleterious effects on PMN adhesion molecule expression and subsequent migration into the peritoneal cavity in a peritonitis model. No studies to date have focused on adhesion molecule expression on circulating and exudative PMNs simultaneously.

The present study indicated that circulating PMNs from the diet-restricted group had lower CD11b/CD18 expression, although only six mice per group were studied in this experiment leaving the potential for type I statistical errors. However, the SEMs for this experiment are relatively tight. CD62L expression on circulating PMNs did not differ significantly between the diet-restricted and ad libitum groups. Exudative PMN number in the diet-restricted group was decreased in association with decreased in CD11b/CD18 expression. The results suggest that malnutrition impairs host defense during peritonitis, at least in part, by decreasing exudative PMN numbers that result from a reduction of CD11b/CD18 expression on circulating PMNs. Moreover, endothelial transmigration regulates neutrophil function through cross-linking of adhesion molecules.10,11CD18 reportedly plays an important role in adhesion-dependent priming of neutrophil functions.11,12 Thus, it is possible that functions of exudative PMNs may be different between the ad libitum and dietrestricted groups. Further study will be needed to clarify the functional alteration of exudative PMNs by diet restriction.

CD11b/CD18, an adhesion-promoting (32 integrin, is constitutively expressed on the plasma membranes of PMNs.9 On activation, additional CD11b/CD18 molecules are rapidly mobilized from intracellular specific granules to the cell surface membrane.13 Although we did not investigate the mechanisms underlying decreased adhesion molecule expression on circulating PMNs in this study, it is possible that malnutrition depressed the synthesis or mobilization of adhesion molecules on circulating PMNs.

This type of malnutrition may decrease circulating insulin-like growth factor-1 (IGF-1) levels,14 elevate circulating free cortisol,15 and blunt the activation of complement systems and proinflammatory cytokine production in response to an inflammatory stimulus.16,17 previous work demonstrated IGF-1 treatment increases beta2 integrin expression on PMNs.18 Cortisol inhibits CD18 expression on leukocytes.19 Activated complement components and tumor necrosis factor (TNF)-alpha stimulate beta2 integrin expression on PMNs and enhance PMN adhesion.20-22

CD62L expressed on the leukocyte surface is also an adhesion molecule regulating leukocyte trafficking in the systemic microcirculation.7 The diet restriction applied herein did not change CD62L expression on circulating PMNs in response to intraperitoneal glycogen installation, regardless of decreased PMN exudation. This observation suggests that CD62L expression on circulating PMNs does not impair host immunity in this malnutrition model. Decreased CD62L expression on exudative PMNs, compared with circulating PMNs, in both the diet-restricted and the ad libitum group may be caused by shedding through transmigration.6

We studied the influence of 1 week of dietary restriction on leukocyte adhesion molecule expression and exudative leukocyte numbers at 4 hours after glycogen installation. Intraperitoneal inoculation of a glycogen solution has been demonstrated to be an adequate model for investigating inflammatory responses.2 One week of dietary restriction in mice reportedly leads to impaired host immunity.24,25 peritoneal macrophages from mice subjected to one week of protein-caloriemalnourishment produced less interleukin-6 or TNF-a in response to lipopolysaccharide stimulation than macrophages from control mice.24 Mice fed a proteinfree diet for 7 days showed significantly reduced survival compared with control mice with a 24% casein diet after Candida albicans challenge.25 With regard to the timing of sacrifice, our preliminary experiments revealed maximum PMN influx into the peritoneal cavity to occur at 4 hours after glycogen injection.

In addition to its effects on PMNs, dietary restriction also decreased circulating monocyte CD18 expression and the number of peritoneal macrophages. Malnutrition appears to affect monocyte function and macrophage influx into the peritoneal cavity.24 However, maximum macrophage influx into the peritoneal cavity reportedly occurs at 12 hours after glycogen administration.23 Further studies focusing on the late phase of inflammation are required to examine the influence of malnutrition on the monocyte/macrophage axis.

In summary, ours is a preliminary study that for the first time has demonstrated that 1 week of dietary restriction reduces the numbers of exudative PMNs at the inflammatory site with decreased expression of beta2-integrin on circulating PMNs. Many questions remain to be answered, including the mechanisms underlying changes in adhesion molecule expression, poststimulation kinetics, and the effects of different durations and degrees of dietary restriction. Functional effects of malnutrition on leukocytes must be clarified in future studies. Nevertheless, our findings imply that nutritional replenishment may improve host defense, at least in part, via enhancing PMN adhesion molecule expression and subsequent PMN exudation into inflammatory sites.


1. Windsor JA, Hill GL: Weight loss of nutrition on the impairment. A basic indicator of surgical risk. Nutrition Surg 207:290-296, 1988

2. Chandra W Kumari S: Effects of nutrition on the immune system. Nutrition 10:207-210, 1994

3. Chandra RK, Chandra S, Ghai OP: Chemotaxis, random mobility, and mobilization of polymorphonuclear leucocytes in malnutrition. J Clin Pathol 29:224-227, 1976

4. Harris MC, Douglas SD, Lee JC, et al: Diminished polymorphonuclear leukocyte adherence and chemotaxis following proteincalorie malnutrition in newborn rats. Pediatr Res 21:542-546, 1987

5. Douglas SD, Schopfer K: Phagocyte function in protein-calorie malnutrition. Clin Exp Immunol 17:121-128, 1974

6. Carlos TM, Harlan JM: Leukocyte-endothelial adhesion molecules. Blood 84:2068-2101, 1994

7. Lewinsohn DM, Bargatze RF, Butcher EC: Leukocyte-endothelial cell recognition: Evidence of a common molecular mechanism shared by neutrophils, lymphocytes, and other leukocytes. J Immunol 138:4313-4321, 1987

8. Smith CW, Rothlein R, Hughes BJ, et al: Recognition of an endothelial determinant for CD18-dependent human neutrophil adherence and transendothelial migration. J Clin Invest 82: 1746-1756, 1988

9. Arnaout MA, Spits H, Terhorst C, et al: Deficiency of a leukocyte surface glycoprotein (LFA-1) in two patients with Mol deficiency. Effects of cell activation on Mol/LFA-1 surface expression in normal and deficient leukocytes. J Clin Invest 74:12911300, 1984

10. Yee J, Giannias B, Kapadia B, et al: Exudative neutrophils. Modulation of microbicidal function in the inflammatory microenvironment. Arch Surg 129:99-105, 1994

11. Liles WC, Ledbetter JA, Waltersdorph AW, et al: Cross-linking of CD18 primes human neutrophils for activation of the respiratory burst in response to specific stimuli: Implications for adhesion-dependent physiological responses in neutrophils. J Leukoc Biol 58:690-697, 1995

12. Flaherty SF, Golenbock DT, Milham FH, et al: CD11/CD18 leukocyte integrins: New signaling receptors for bacterial endotoxin. J Surg Res 73:85-89, 1997

13. Todd RFd, Arnaout MA, Rosin RE, et al: Subcellular localization of the large subunit of Mol (Mol alpha; formerly gp 110), a surface glycoprotein associated with neutrophil adhesion. J Clin Invest 74:1280-1290, 1984

14. Phillips LS, Goldstein S, Gavin Jr: Nutrition and somatomedin. XVI: Somatomedins and somatomedin inhibitors in fasted and refed rats. Metab Clin Exp 37:209-216, 1988

15. Ausman LM, Gallina DL, Hegsted DM: Protein-calorie malnutrition in squirrel monkeys: Adaptive response to calorie deficiency. Am J Clin Nutr 50:19-29, 1989

16. Mulligan MS, Yeh CG, Rudolph AR, et al: Protective effects of soluble CRl in complement- and neutrophil-mediated tissue injury. J Immunol 148:1479-1485, 1992

17. Mulligan MS, Lentsch AB, Miyasaka M, et al: Cytokine and adhesion molecule requirements for neutrophil recruitment during glycogen-induced peritonitis. Inflamm Res 47:251-255, 1998

18. Bjerknes R, Aarskog D: Priming of human polymorphonuclear neutrophilic leukocytes by insulin-like growth factor I: Increased phagocytic capacity, complement receptor expression, degranulation, and oxidative burst. J Clin Endocrinol Metab 80:19481955, 1995

19. Burton JL, Kehrli ME Jr, Kapil S, et al: Regulation of L-selectin and CD18 on bovine neutrophils by glucocorticoids: Effects of cortisol and dexamethasone. J Leukoc Biol 57:317-325, 1995

20. Condliffe AM, Chilvers ER, Haslett C, et al: Priming differentially regulates neutrophil adhesion molecule expression/function. Immunology 89:105-111, 1996

21. Gamble JR, Harlan JM, Klebanoff SJ, et al: Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci USA 82:8667-8671, 1985

22. Carlos TM, Harlan JM: Membrane proteins involved in phagocyte adherence to endothelium. Immunol Rev 114:5-28, 1990

23. Giorgi R, Pagano RL, Dias MA, et al: Antinociceptive effect of the calcium-binding protein MRP-14 and the role played by neutrophils on the control of inflammatory pain. J Leukoc Biol 64:214220, 1998

24. McCarter MD, Naama HA, Shou J, et al: Altered macrophage intracellular signaling induced by protein-calorie malnutrition. Cell Immunol 183:131-136, 1998

25. Hill AD, Naama H, Shou J, et al: Antimicrobial effects of granulocyte-macrophage colony-stimulating factor in protein-energy malnutrition. Arch Surg 130:1273-1277, 1995

Shigeo Ikeda, MD*; Hideaki Saito, MDt; Tomomi moue, MD*; Kazuhiko Fukatsu, MD*; Ilsoo Han, MD*; Satoshi Furukawa, MD*; Takeaki Matsuda, MD*; and Akio Hidemura, MD*

From the *Department of Sugery, Faculty of Medicine, ^Surgical Center, The University of Tokyo, Japan

Received for publication, October 4, 1999. Accepted for publication, April 6, 2000.

Correspondence and reprint requests: Shigeo Ikeda, MD, Department of Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Electronic mail may be sent to

*Presented in part and rewarded as an ESPEN travel fellowship at ESPEN 99 Congress, on September 5, 1999, Stockholm, Sweden.

Copyright American Society for Parenteral and Enteral Nutrition Sep/Oct 2000
Provided by ProQuest Information and Learning Company. All rights Reserved

Return to Leukocyte adhesion deficiency syndrome
Home Contact Resources Exchange Links ebay