Clinical Conditions Associated With Defective Polymorphonuclear Leukocyte Chemotaxis Paul G. Quie, MD, and K. Lynn Cates, MD

Impressive numbers of clinical conditions are associated with defective leukocyte chemotaxis. In many, this cellular dysfunction is associated with other abnormalities of the immune response, but in others abnormal chemotactic responsiveness of leukocytes is the only abnormality of function identified in the laboratory. Patients are usually selected for study because of unusually severe, recurrent infections or poor response to antimicrobial agents, and therefore a frequent association between abnormality of chemotaxis and infection would be expected. Many patients demonstrate abnormal chemotaxis during remissions as well as during infections, and there seems little doubt that abnormality of chemotaxis is related to susceptibility to infections. Partial classification of disorders of chemotaxis was attempted. Major abnormalities are found when there is a primary cellular disorder or cell-directed inhibitors of chemotaxis are found. Less marked abnormalities are found when chemotactic factors are deficient. (Am J Pathol 88:711-726, 1977)

PATIENTS WITH GRA.NULOCYTE DISORDERS have frequent infections, and the clinical manifestations are quite similar whether the disorder is insufficient numbers of cells or cell dysfunction. Infections terid to be prolonged, there is poor response to appropriate antibiotics, and recurrent infections are the rule. Rapid migration into tissues invaded bv bacteria is a granulocyte function essential for host antibacterial defense. Patients with this granulocyte dysfunction may be infected by any of a wide spectrum of microorganisms. Staphylococcus aureus is the most frequent bacterial species identified in infectious lesions in these patients, but gram-negative enteric bacteria and fungal species as well as Staphylococcus epidermidis are frequently responsible for recurrent and prolonged disease. Infections most typicallv involve the skin, and regional adenitis is common. Pneumonia occurs frequently, but bacteremia and septicemia are uncommon. It is possible to contrast the etiologic agents and kinds of infections in patients with phagocvtic disorders with those in patients with abnormal immunoglobulin response. Patients with hypogammaglobulinemia, for From the Department of Pediatrics, Universitv of Minnesota School of Medicine. \Minneapolis. MI innesota Presented at the sixtv-first Annual Meeting of the Federation of American Societies for Experimental Biology. Chicago. III., April 4, 1977 Supported by Grants AI-08821. AI-06931, and AI-12402 from the National Institute of Allergy and Infectious Disease. Address reprint requests to Dr Paul G Quie. Department of Pediatrics. Unisersitv of Minnesota Hospitals. Box 4&3 Mavo Memorial Building. Minneapolis, MN 55455 711

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example, have frequent infections with S. pneumoniae, Hemophilus influenzae, and Group A streptococci. Septicemia or meningitis may be recurrent in these patients before specific replacement therapy is applied, whereas septicemia and meningitis are rare in patients with granulocyte dysfunction. Patients with defective leukocyte chemotaxis have purulent lesions and, indeed, there may be copious fluid in absesses involving the lungs or subcutaneous tissue in these patients. Established infections occur because of delay in accumulation of leukocytes; however, subsequent systemic spread may be prevented by the eventual migration of neutrophils and monocytic cells. An impressive number of clinical conditions with abnormal neutrophil chemotactic responsiveness has been described in the past decade. In most of these clinical situations, abnormal chemotaxis has been a result of an "intrinsic" neutrophil dysfunction, i.e., neutrophils function abnormally even when suspended in normal serum. Furthermore, the patients' serum or plasma does not compromise the chemotaxis of normal neutrophils. Defective generation of chemotactic factors (primarily complement components) has been described in patients, and certain patients have abnormal neutrophil chemotaxis because of circulating inhibitors. Clinical situations with abnormal chemotaxis and clinical manifestations in these situations will be reviewed in this presentation. Clinical Conditions With Cellular Defects of Granulocyte Chemotaxis There is an ever-growing list of patients with abnormal chemotaxis, and some of them have associated defects of cellular function. Some of these clinical conditions are listed in Table 1. Ward and Schlegel described a patient in 1969 with defective leukotaxis and with recurrent infections.' The neutrophils from this patient were deficient in bactericidal capacity for gram-negative bacteria as well as defective in chemotaxis, and the clinical syndrome described was similar Table 1-Clinical Conditions With Abnormal Chemotaxis and Other Defects in Leukocyte Function

Chediak-Higashi syndrome Hypogammaglobulinemia Chronic mucocutaneous candidiasis Mannosidosis Severe burns

Overwhelming infection Bone marrow transplantation Actin dysfunction Chronic granulomatous disease (occasionally) Protein-calorie malnutrition

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to chronic granulomatous disease. Most patients with chronic granulomatous disease have normal neutrophil chemotaxis, but this patient demonstrated both abnormal chemotaxis and abnormal intracellular killing. Shortly after that report, 2 children with neutropenia, depressed neutrophil mobility, and recurrent infection were reported and this constellation of findings was termed lazy leukocyte syndrome.2 These 2 children were severely neutropenic but had normal myeloid precursors and mature neutrophils in their bone marrow. Their illnesses were characterized by gingivitis and stomatitis and recurrent upper respiratory infections. The only immunologic or inflammatory abnormality identified in these children was defective chemotactic responsiveness and random mobilitv of their neutrophils. This neutrophil abnormality could not be corrected by fresh normal plasma, and there was no lack of chemotactic factors and no inhibitor in the patient's plasma, so there was a cellular defect of neutrophil function. The patients' leukocytes demonstrated normal capacity for phagocytosis and bacterial killing and abnormal membrane receptors for chemotactic factors was postulated. More recently, a 58-year-old male with recurrent severe protracted subcutaneous infections and poor wound healing was found to have defective neutrophil chemotaxis.3 Neutrophil abnormalities consistent with chronic granulomatous disease were also found, i.e., defective neutrophil bactericidal capacity and absent nitroblue tetrazolium reduction during phagocytosis. Chromosome analysis revealed deletion of a segment of chromosome 16, suggesting that this chromosome may be an important genetic locus for factors influencing leukocyte function. A male infant with abnormal actin polymerization with defective granulocyte locomotion and defective phagocytosis has been described.4 Still another combination of intrinsic neutrophil functional defects was identified in a 4-year-old boy who suffered nine episodes of x-ray-documented pneumonia before his second birthday.5 The patient's neutrophils did not phagocytize staphylococci, and defective chemotaxis of his neutrophils was demonstrated in vitro and in vivo with little migration to skin windows. There was a paucity of neutrophils in the skin lesions, and markedly delayed wound healing complicated his clinical course. The patient also had X-linked hypogammaglobulinemia, and severe susceptibility to infections was probably a consequence of defective humoral as well as phagocytic function. Patients with Chediak-Higashi syndrome have several functional abnormalities of their neutrophils including defective chemotaxis." The diagnosis of Chediak-Higashi syndrome is made by identification of leukocytes with giant cytoplasmic lyosomal granules, and the chemotactic

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defect has been postulated to result from the giant granules preventing the neutrophils from squeezing through small spaces. Recent evidence, however, suggests that there may be a metabolic defect in ChediakHigashi leukocytes as well which inhibits neutrophil migration. Boxer et al. found extremely elevated levels of intracellular cyclic adenosine monophosphate (AMP) in leukocytes of a patient with Chediak-Higashi syndrome.7 Ascorbic acid at a 200-mg daily dose brought about a sharp reduction in the levels of leukocyte cyclic AMP in this patient, and there was convincing improvement in the patient's neutrophil chemotactic responsiveness.

We have recently had an opportunity to study the immunologic function of a 3.5-year-old white female with mannosidosis.8 This storage disease results from deficiency of acidic a-mannosidase activity, and mannose-rich material accumulates in cells, including the circulating leukocytes. The diagnosis of mannosidosis is made by demonstrating enzyme deficiency in plasma, leukocytes, and skin fibroblasts. Recurrent infections were a major problem in this patient. She had chronic otitis media with marked hearing loss and was hospitalized four times for severe upper respiratory infections before her second birthday. During her third year of life she was nearly continuously hospitalized with otitis media and pneumonia, and her terminal illness was severe infiltrative lung disease with progressive respiratory failure. Viral cultures revealed adenovirus Type 7 from urine, stool, and throat cultures and from lung tissue obtained at autopsy. There was a generally depressed immunologic response in this patient. Immunoglobulin levels were low and there was a decreased response of lymphocytes to phytohemagglutinin. The most striking defect was in neutrophil chemotactic responsiveness. There was also delayed phagocytosis of S. aureus and Escherichia coli. Normal nitroblue tetrazolium reduction by the patient's neutrophils was evidence that oxidative metabolic responsiveness was normal even though locomotion was abnormal. It is interesting to speculate that abnormal mannose material in this patient may have interfered with leukocyte membrane function or with the process of cell locomotion. However, it cannot be stated with certainty that the patient's systemic adenovirus did not contribute to the demonstrated neutrophil dysfunction. Defective chemotaxis in another child with mannosidosis has also been reported.9 Patients with defective neutrophil chemotaxis frequently have severe dermatologic abnormalities. Pincus et al. recently described a 4-yearold child with ichthyosis, severe subcutaneous abscesses, and depressed neutrophil chemotaxis.10 The organisms recovered from infected lesions

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included S. aureus, Candida albicans, and multiple gram-negative enteric bacteria. The frequent infections in this patient were probably related to the humoral epidermal barrier, since "water-logged" skin was noted at birth, but the severitv of the infectious process mav have been related to defective neutrophil chemotaxis. The authors noted that only IgM was produced in response to antigenic challenge in this patient, and there was an extremely high level of serum IgE, which suggests that lymphocyte suppressor activity may have been present in this patient. The association of ichthvosis and depressed neutrophil chemotaxis was also noted in 3 children with persistent Trichophyton rubrum infections."1 One of the children suffered a pelvic abscess, and recurrent mild infections were noted in the other children. The fathers of these children also had chronic dermatitis (frequently infected) and depressed neutrophil chemotaxis. Another list of clinical conditions with cellular defects of granulocyte chemotaxis without gross abnormality of other leukocyte function is found in Table 2. Patients with extremely elevated levels of IgE and recurrent staphylococcal infections have defective neutrophil chemotaxis.'2-'5 In 1973, Clark et al. described an 11-vear-old girl with depressed neutrophil chemotaxis and serum IgE levels ranging from 19,000 to 23,000 ng/ml. She had developed pustular dermatitis at 2 weeks of age and staphylococcal pneumonia at ages 3, 6, 7, and 9 years. Frequent subcutaneous abscesses and lymph node abscesses required surgical drainage. The patient also had monilial mouth lesions and immunologic abnormalities characteristic of the mucocutaneous candidiasis syndrome, i.e., a negative skin test and lack of in vitro lymphocyte responsiveness to Candida antigen.'2 Shortly after that patient was described, 3 additional children, ages 18 months to 2 years, with depressed neutrophil chemotaxis, extremely elevated serum IgE, eczema, and recurrent staphylococcal abscesses were reported.'3 The age of onset and the skin disease were similar in all of these patients. Table 2-Cellular Defects in Granulocyte Chemotaxis Newborn infants Measles Down's syndrome Chronic renal failure (on dialysis) Periodontitis Hypophosphatemia Diabetes mellitus Rheumatoid arthritis "Lazy leukocyte" syndrome Icthyosis Hyperimmunoglobulin E (Job's syndrome) Hyperimmunoglobulin A

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Eczema developed by 2 months of age, and abscesses requiring surgical drainage were present by 6 months of age. The children had extensive weeping dermatitis with particularly extensive involvement of the face and scalp. Staphylococci and Group A streptococci were frequently recovered from infected lesions. In addition to cellulitis and subcutaneous abscesses, staphylococcal pneumonia occurred in 1 child and a deep staphylococcal abscess of the gluteus muscle in another child. Candida lesions were not observed in these children, and all studies of humoral immune responses, lymphocyte response, and neutrophil phagocytic and bactericidal activities were normal. A mother and daughter with extremely elevated serum IgE levels, eczema, and severe staphylococcal abscesses involving the lungs, retropharyngeal space and, in the mother, recurrent breast abscesses have been reported.14 In these patients a persistent Candida infection of the mouth and intertriginous areas of the body were also present. The daughter had recurrent subcutaneous lesions requiring incision and drainage, and a large staphylococcal lung abscess developed during her first 18 months of life. S. aureus was cultured from material obtained when the lung abscess was surgically drained; after prolonged antimicrobial therapy, there was complete recovery. This report and others suggest a hereditary basis for some of the clinical conditions associated with defective chemotaxis. Extremely elevated levels of IgE and defective neutrophil chemotactic function are also present in patients with Job's syndrome.15 This syndrome is characterized by recurrent severe staphylococcal abscesses and suppurative lymphadenitis without the usual concomitants of inflammation, redness, heat, and pain. A 16-year-old patient with Job's syndrome was 2 years old when treated by one of the authors (PGQ) for a large "cold" abscess due to S. aureus involving the forehead. She has received nearly continuous antistaphylococcal therapy for the past 14 years, and infections have been infrequent and superficial. Eczematoid lesions of her skin persist, and she has recently developed Candida lesions of her mouth and changes in her finger nails typical of chronic Candida infection. The patients described with this syndrome have all been females with red hair and severe atopic dermatitis. The serum IgE levels ranged from 6,000 to 19,500 IU, and a profound defect of neutrophil chemotaxis is usually present. It is interesting to speculate that the clinical manifestation of "cold" abscesses and defective neutrophil chemotaxis may be related to the same circulating factor. There is little correlation between the levels of circulating IgE and leukocyte chemotactic responsiveness. Certain patients with elevated IgE levels may have normal neutrophil chemotaxis, and abnormal neutrophil chemotaxis may be present in pa-

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tients with minimal or no elevation of immunoglobulin E levels. In the individual patient, there is a definite correlation between the severitv of atopic dermatitis and depression of chemotaxis, however. Patients with hyperimmunoglobulin E syndrome are not rare. Dahl et al. described 11 patients with depressed chemotaxis, eosinophilia and recurrent staphylococcal abscesses, eczema, and hyperimmunoglobulin E,'6 and Rogge and Hanifin described 7 additional patients with increased infections, severe atopic dermatitis, and polymorphonuclear and mononuclear leukocyte chemotaxis deficiency.'7 Patients with the most severe atopic dermatitis had the highest incidence of infection and the most severe abnormality of leukocyte function. Infections included Staphylococcus aureus, dermatophytes, and Herpes hominus virus. The infections were persistent and frequently recurred, and in several patients depressed chemotaxis could be demonstrated only during severe flares of dermatitis. We have made similar observations in our patients, and it would appear that mechanisms involved in severe atopic dermatitis may also be related to depressed neutrophil chemotaxis. Histamine has been demonstrated to inhibit release of Iysosomal enzymes from leukocytes, and these leukocyte enzymes are involved in the inflammatory response."8 Histamine has also been shown to be one of the compounds which can raise intracellular levels of cyclic AMP and reduce the chemotactic response of human neutrophils. Bjorksten and Lundmark reported defective neutrophil chemotaxis and recurrent infection in 4 siblings with increased levels of circulating IgA.'9 All of the patients had recurrent pneumonia in addition to recurrent skin infections, otitis media, and staphylococcal abscesses. The association between depressed neutrophil chemotaxis, hvperimmunoglobulin A, and recurrent infections observed by these authors is especially intriguing since it has recentlv been shown that polymeric molecules of IgA are cytophilic for human neutrophils and markedly suppress chemotaxis." These clinical and experimental observations suggest that IgA immunoglobulins may be related to neutrophil chemotaxis abnormalities. Patients with diabetes mellitus have mildly depressed neutrophil chemotaxis.2' Chemotaxis in most diabetic patients is near normal, but manv diabetic patients demonstrate neutrophil chemotactic responsiveness 2 standard deviations below normal. We have observed a similar depression of chemotactic responsiveness in patients with juvenile onset diabetes mellitus.22 There was much overlap between the chemotactic responsiveness of diabetic patients and normal controls, but when 30 patients with juvenile onset diabetes mellitus were compared with 30 agematched controls, the difference in chemotaxis was statistically signifi-

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cant. The decrease leukotactic response did not correlate with age of patients, degree of control, serum concentration of glucose, cholesterol, triglycerides, or creatinine. We also confirmed the observation of Mowat and Baum that incubation of diabetic leukocytes in 100 units of insulin in a glucose-containing medium improved the cells' responsiveness to a chemotactic stimulant. The question concerning the role of exogenous insulin or metabolic abnormalities associated with diabetes on leukocyte function has been partially answered by a recent study.23 Fifty-two first degree relatives of patients with diabetes who had never received exogenous insulin were examined. The chemotactic index was significantly lower in these firstdegree relatives than in healthy persons who were not related to diabetics. This study suggests that a cellular membrane defect associated with diabetes may also be associated with abnormal neutrophil chemotactic responsiveness. A transient depression of granulocyte chemotaxis and random migration was found in 35 children with measles.2' There was return of leukotactic function to normal approximately 10 days after onset of the measles rash and improvement of leukocyte function coincided with the patients' return to a normal clinical condition. A transient depression of leukocyte chemotactic responsiveness was also noted in patients with allergic rhinitis and recurrent staphylococcal furunculosis.26 These patients had normal concentrations of IgE, and there was normal chemotaxis when the patients were clinically well. When allergic symptoms appeared, there was depressed neutrophil chemotaxis and a predictable onset of staphylococcal abscesses. Certain patients who have undergone bone marrow transplantations for leukemia or aplastic anemia have severely depressed neutrophil chemotactic responsiveness.26 Depressed chemotaxis was found in 18 of 34 patients who had received transplants, and these 18 patients were the ones who were undergoing graft-versus-host reactions or were receiving antithymocyte globulin. The patients with defective chemotaxis suffered significantly more severe bacterial infections than did patients with normal neutrophil chemotaxis. McCall and his colleagues studied neutrophil chemotactic responsiveness and other neutrophil functions in a series of 22 patients with severe bacterial infections and a mortality rate of 30%.27 In all of these patients, more than 90% of the peripheral leukocytes had toxic granulation (abnormally staining azurophil granules), D'ohle bodies (aggregates of rough endoplasmic reticulum), or cytoplasmic vacuoles. All patients had a marked reduction in chemotactic responsiveness. In addition, there was

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reduction in random migration and in phagocvtosis of staphylococci, reflecting a general depression of leukocvte locomotion. This disorder is listed in Table 1. We have studied an equal number of younger patients (mean age, 11.5 years) with less severe bacterial infections and have found that neutrophil chemotaxis is increased rather than depressed." In our patients, the bacterial infections responded to appropriate antibiotic therapy, there was no mortality, and although not thoroughlv documented, there was less morphologic abnormality in the peripheral neutrophils. The mean leukotactic index of the patients was more than twice that of age-match, uninfected controls, and there was return to normal chemotactic response within 7 to 14 davs after appropriate antibiotic therapy. Patients with severe bums (greater than 30% second and third degree) may have neutrophil chemotactic defects which persist for as long as several weeks.' As patients receive grafts and return to a normal clinical state, there is improvement in neutrophil chemotactic responsiveness. We have not found depressed neutrophil chemotaxis to be useful for judging prognosis.

Depressed chemotactic responsiveness has also been observed in patients with chronic renal failure, especially after prolonged hemodialvsis.30 This is not a constant phenomenon in all patients on chronic dialysis, but there is a direct correlation between the number of dialysis treatments and the degree of depression of neutrophil chemotactic responsiveness. Patients receiving chronic hemodialvsis are usuallv susceptible to severe infections, and although there are several predisposing factors which provide ready access for bacteria and fungi, defective neutrophil function mav contribute to their susceptibility. Delaved chemotactic responsiveness has been reported in children with kwashiorkor.31 Clinicallv these children have,marked reduction in body weight, apathy, irritabilitv, edema, hepatomegalv, and necrotizing skin lesions. Susceptibility to bacterial, fungal, and viral infections is increased, and there is frequently a paucity of leukocvtes in lesions despite the presence of pyogenic microorganisms.32 Schopfer and Douglas have found diminished polymorphonuclear leukocvte chemotactic activitv at earlv time intervals in children with protein-calorie malnutrition, but a normal number of neutrophils had migrated completelv through filters bv 180 minutes' incubation.3' It is uncertain if this leukocvte abnormalitv contributes to increased susceptibility to infection. Miller has reported decreased chemotactic responsiveness in newbom infants.33 Not onlv do neutrophils from newborns fail to migrate normallv toward the usual attractants, but their serum fails to generate

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Table 3-Chemotactic Factor Abnormalities

Deficiency of Cl, C4, C2 Deficiency of C3, C5 C5 dysfunction Immunoglobulin deficiency Defective properdin pathway Lymphokine dysfunction

normal chemotactic activity. The cellular chemotactic defect may be related to decreased newborn polymorphonuclear leukocyte membrane deformability.34 Monocytes from neonates also have significantly decreased chemotactic responsiveness.35 Abnormal leukocyte locomotion may contribute to the newborns' decreased ability to localize infections; however, most newborns acquired a resident microbial flora uneventfully in spite of a generally immature inflammatory response. Deficiency of Chemotactic Factors Abnormal leukotaxis may also result from abnormality of potential chemotactic factors (Table 3). Defects in the complement system may result in diminished serum chemotactic factor activity. For example, when Clr-deficient serum was studied, chemotactic activity was generated more slowly than in normal serum, but full chemotactic activity was eventually generated.38 No relationship between delayed chemotactic factor generation and susceptibility to infection has been established in patients with dysfunction of the early complement components; however, an increased incidence of inflammatory disease such as systemic lupus erythematosus and dermatomyositis has been described.37 A patient with Klinefelter's syndrome, with a history of repeated pyogenic infections and a low serum C3 level, was found to lack serum chemotactic factor activity.38 Activity could be restored by addition of normal serum, but not by purified C3. Another patient with congenital absence of the third component of complement had serious infections with encapsulated gram-positive and gram-negative bacteria, and her serum lacked chemotactic, opsonic, and bactericidal activity.39 A 19-year-old female patient with C5 deficiency and lupus erythematosus since age 11 years has recently been described.40'41 The patient's infections included oral and vaginal moniliasis, infected cutaneous and subcutaneous ulcers, chronically draining sinus tracts, sepsis, and meningitis. A markedly impaired ability to generate chemotactic activity was demonstrated in her serum. Family members heterozygous for C5 deficiency were able to generate normal chemotactic activity. Dysfunctional C5 has also been described in patients with recurrent infections whose sera were incapable of generating normal chemotactic activity.42

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Two patients with C7 deficiencv have been reported.''" Serum from 1 of these patients did not generate chemotactic activity normally, but addition of C7 in vitro corrected the defect. Serum from the other patient was capable of normal chemotactic activitv. Raynaud's phenomenon was noted in the patient with chemotactic deficiency, but there was no historv of increased susceptibility to infections. From these clinical observations, it is possible to generalize that the most critical complement components in terms of chemotactic factor function are C3 and C5. A definite relationship between susceptibility to infection and deficiency of other complement components is difficult to establish. However, absence of other complement components may be associated with other diseases. Inhbitos of Chemotaxis Clinical conditions with circulating inhibitors of chemotaxis are listed in Table 4. The clinical presentation of patients with circulating inhibitors of leukotaxis is similar to that of patients with intrinsically defective leukocv,te mobility. A 7-vear-old bov has been described with a cell-directed inhibitor of chemotaxis who suffered recurrent pyoderma, otitis media, pneumonia, and purulent rhinitis since the age of 1 year." His neutrophils had depressed chemotaxis when incubated with autologous serum but migrated normallv when washed and suspended in normal serum. It is of interest that the patient had extremely elevated levels of circulating IgA and IgG and a high titer of rheumatoid factor. An 8-month-old child with cytomegalovirus infection, recurrent pneumonias, persisting pulmonary infiltrates, and staphvlococcal skin lesions was found to have markedly depressed chemotactic responsiveness.' This was only observed in autologous plasma, and chemotaxis of control neutrophils was also depressed in this plasma, thus demonstrating an inhibitor of leukotaxis. When Table 4-Clinical Conditions With Circulating Inhibitors of Chemotaxis Inhibitors of granulocytes Wiskott-Aldrich syndrome IgA myeloma Malignancy Severe eczema Chronic mucocutaneous candidiasis Inhibitors of chemotactic factors Liver cirrhosis

Sarcoidosis Leprosy Hodgkin's disease Uremia

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plasma was given, there was striking clinical improvement, suggesting that the patients lacked a normal antagonist of their respective serum inhibitors of chemotaxis. An association between the presence of acute illnesses with leukocytosis, negative skin test response to recall antigens, and a serum chemotaxis inhibitor has been noted.47 Sixteen patients demonstrated this combination of clinical and laboratory findings during illness with return of normal chemotactic activity and skin test responsiveness when clinical improvement occurred. The serum fractions with inhibitor activity had characteristics associated With immunoglobulin A. A 10-year-old black female with onset of eczema in the early months of life, recurrent staphylococcal abscesses, gonococcal conjunctivitis, and repeated episodes of bronchopneumonia was found to have depressed chemotaxis. The patient's serum IgA was markedly elevated at 1.2 g/ml, and an IgA and IgM containing cryoglobulin was found in the patient's serum. There was no inhibition of chemotactic factors by the patient's serum, and the patient's neutrophil chemotaxis was restored by incubation in control plasma, suggesting a cell-directed inhibitor of chemotaxis. A patient with chronic mucocutaneous candidiasis had markedly depressed chemotactic responsiveness of granulocytes suspended in her own plasma but not in control plasma.49 Normal neutrophils were also inhibited by the patient's plasma, and partial characterization of this inhibitor revealed that it had several properties in common with IgG. Children with Wiskott-Aldrich syndrome have plasma with inhibits chemotaxis of normal monocytes.50 Lymphocytes from patients with Wiskott-Aldrich syndrome produce much more lymphocyte-derived chemotactic factor than normal lymphocytes, and it is postulated that leukocytes in patients with Wiskott-Aldrich syndrome are constantly exposed to high levels of the lymphocyte-derived chemotactic factor and are "deactivated." The inhibitors of chemotaxis described above directly affect cellular responsiveness, while other inhibitors depress chemotaxis by inactiviting circulating chemotactic factors. These inhibitors may be naturally occurring plasma proteins or products of an inflammatory response, and chemotaxis is decreased only when these substances are present in high concentration. For example, patients with Hodkgin's disease have three to five times higher levels of circulating chemotactic factor inhibitor with properties similar to inhibitors found in control serum.5' Patients with lepromatous leprosy and sarcoidosis also have increased levels of circulating chemotactic factor inactivator with similar properties to that in patients with Hodgkin's disease.52 53 Patients with Hodgkin's disease, leprosy, and

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sarcoidosis usually are incapable of developing delayed skin hypersensitivity responses which may be related to circulating inhibitors which prevent migration of leukocytes to inflammatory sites. Clinically, these patients are highly susceptible to bacterial, viral, and fungal infections, and it is probable that the combination of multiple intrinsic leukocyte defects as well as excessive circulating inflammatory inhibitors contribute to this increased susceptibility. Patients with alcoholism and cirrhosis also have a greatly increased susceptibility to serious bacterial infections." There are frequent life-threatening infections in these patients which may be related to their abnormal inflammatory response. References 1. Ward PA, Schlegel RJ: Impaired leucotactic responsiveness in a child with recurrent infections. Lancet 2:344-347, 1969 2. Miller ME, Oski FA, Harris MB: Lazv-leucocyte svndrome: A new disorder of neutrophil function. Lancet 1:665-669, 1971 3. Singh H, Boyd E, Hutton MM, Wilkinson PC, Peebles Brown DA, Ferguson-Smith MA: Chromosomal mutation in bone marrow as cause of acquired granulomatous disease and refractorv macrocvtic anaemia. Lancet 1:873-879, 1972 4. Boxer LA, Hedley-Whvte ET, Stossel TP: Neutrophil actin dvsfunction and abnormal neutrophil behavior. N Engl J Med 291:1093-1099, 1974 5. Steerman RL, Snyderman R, Leikin SL, Colten HR: Intrinsic defect of the polymorphonuclear leucocvte resulting in impaired chemotaxis and phagocvtosis. Clin Exp Immunol 9:939-946, 1971 6. Clark RA, Kimball HR: Defective granuloc,te chemotaxis in the Chediak-Higashi svndrome. J Clin Invest 50:2645-2652, 1971 7. Boxer LA, Watanabe AM, Rister M, Besch HR Jr, Allen J, Baehner RL: Correction of leukocvte function in Chediak-Higashi syndrome by ascorbate. N Engl J Med 295:1041-1045, 1976 8. Desnick RJ, Sharp HL, Grabowski GA, Brunning RD, Quie PG, Sung JH, Gorlin RJ, Ikonne JU: Mannosidosis: Clinical, morphologic, immunologic, and biochemical studies. Pediatr Res 10:985-996, 1976 9. Gallin JI, Wright DG, Fauci AS, Rosenwasser LJ, Chusid MJ, Taylor HA, Thomas G, Libaers I, Shapiro LJ, Neufeld EF: Defective leukocvte chemotaxis in mannosidosis. Clin Res 24:344A, 1976 10. Pincus SH, Thomas IT, Clark RA, Ochs HD: Defective neutrophil chemotaxis with variant ichthyosis, hvperimmunoglobulinemia E, and recurrent infections. J Pediatr 87:908-911, 1975 11. Miller ME, Norman ME, Koblenzer PJ, Schonauer T: A new familial defect of neutrophil movement. J Lab Clin Med 82:1-8, 1973 12. Clark RA, Root RK, Kimball HR, Kirkpatrick CH: Defective neutrophil chemotaxis and cellular immunitv in a child with recurrent infections. Ann Intern Med 78:515-519, 1973 13. Hill HR, Quie PG: Raised serum-IgE levels and defective neutrophil chemotaxis in three children with eczema and recurrent bacterial infections. Lancet 1:183-187, 1974 14. Vran Scov RE, Hill HR, Ritts RE Jr, Quie PG: Familial neutrophil chemotaxis defect, recurrent bacterial infections, mucocutaneous candiasis, and hvperimmunoglobulinemia E. Ann Intern Med 82:766-771, 1975 15. Hill HR, Ochs HD, Quie PG, Pabst HF, Klebanoff SJ, Wedgwood RJ: Defect in

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neutrophil granulocyte chemotaxis in Job's syndrome of recurrent "cold" staphylococcal abscesses. Lancet 2:617-619, 1974 Dahl MV, Greene WH Jr, Quie PG: Infection, dermatitis, increased IgE, and impaired neutrophil chemotaxis. Arch Dermatol 112:1387-1390, 1976 Rogge JL, Hanifin JM: Immunodeficiencies in severe atopic dermatitis: Depressed chemotaxis and lymphocyte transformation. Arch Dermatol 112:1391-1396, 1976 Kelly MT, White A: Histamine release induced by human leukocyte lysates: Reabsorption of previously released histamine after exposure to cyclic OMP-active agents. J Clin Invest 52:1834-1840, 1973 Bjorksten B, Lundmark KM: Recurrent bacterial infections in four siblings with neutropenia, eosinophilia, hyperimmunoglobulinemia A, and defective neutrophil chemotaxis. J Infect Dis 133:63-71, 1976 Van Epps, DE, Williams RC Jr.: Suppression of leukocyte chemotaxis by human IgA myeloma components. J Exp Med 144:1227-1242, 1976 Mowat AG, Baum J: Chemotaxis of polymorphonuclear leukocytes from patients with diabetes mellitus. N Engl J Med 284:621-627, 1971 Hill HR, Sauls HS, Dettloff JL, Quie PG: Impaired leukotactic responsiveness in patients with juvenile diabetes mellitus. Clin Immunol Immunopathol 2:395-403, 1974 Molenaar DM, Palumbo PJ, Wilson WR, Ritts RE Jr: Leukocyte chemotaxis in diabetic patients with their nondiabetic first-degree relatives. Diabetes 25 (Suppl 2):880-883, 1976 Anderson R, Sher R, Rabson AR, Koornhof HJ: Defective chemotaxis in measles patients. S Afr Med J 48:1819-1820, 1974 Hill HR, Williams PB, Krueger GG, Janis B: Recurrent staphylococcal abscesses associated with defective neutrophil chemotaxis and allergic rhinitis. Ann Intern Med 85:39-43, 1976 Clark RA, Johnson FL, Klebanoff SJ, Thomas ED: Defective neutrophil chemotaxis in bone marrow transplant patients. J Clin Invest 58:22-31, 1976 McCall CE, Caves J, Cooper R, DeChatelet L: Functional characteristics of human toxic neutrophils. J Infect Dis 124:68-75, 1971 Hill HR, Gerrard JM, Hogan NA, Quie PG: Hyperactivity of neutrophil leukotactic responses during active bacterial infection. J Clin Invest 53:996-1002, 1974 Faville RJ, Quie PG: Unpublished observations Greene WH, Ray C, Mauer SM, Quie PG: The effect of hemodialysis on neutrophil chemotactic responsiveness. J Lab Clin Med 88:971-974, 1976 Schopfer K, Douglas SD: Neutrophil function in children with kwashiorkor, J Lab Clin Med 88:450-461, 1976 Scrimshaw NS, Taylor CE, Gordon JE: Interactions of nutrition and infection. WHO Monogr Ser 57:60-142, 1968 Miller ME: Chemotactic function in the human neonate: Humoral and cellular aspects. Pediatr Res 5:487-492, 1971 Miller ME: Developmental maturation of human neutrophil motility and its relationship to membrane deformability. The Phagocytic Cell in Host Resistance. Edited by JA Bellanti, DH Dayton. New York, Raven Press, 1975, pp 295-307 Orlowski JP, Siegar L, Anthony BF: Bactericidal capacity of monocytes of newborn infants. J Pediatr 89:797-801, 1976 Gallin JI: Abnormal chemotaxis: Cellular and humoral components.34 pp 227-248 Ruddy S, Gigli I, Austen KF: The complement system of man. N Engl J Med 287:592-596, 1972 Alper CA, Abramson N, Johnston RB Jr, Jandl JH, Rosen FS: Increased susceptibilitv to infection associated with abnormalities of complement-mediated functions and of the third component of complement (C3). N Engl J Med 282:349-358, 1970

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39. Ballow- NM, Shira JE Harden L, Yang SY, Day NK: Complete absence of the third component of complement in man. J Clin Invest 56:703-710. 1975 40. Rosenfeld SI, Baum J, Steigbigel RT, Leddy JP: Hereditary deficiency of the fifth component of complement in man. II. Biologic properties of C6-deficient human serum. J Clin Invest 5 7:163-1643. 1976 41. Rosenfeld SI, Kelly NME. Leddy JP: Hereditary deficiency of the fifth component of

42. 43. 44. 43. 46.

complement in man. I. Clinical, immunochemical and family studies. J Clin Invest 57: 1626-16.34, 1976 Miller ME. Nilsson UF: A familial deficiency of the phagocv-tosis-enhancing activity of serum related to a dysfunction of the fifth component (C5). N EngI J Med 282:354-358, 1970 Bover JT, Gall EP, Norman ME, Nilson UR, Zimmerman TS: Hereditary deficiency- of the seventh component of complement. J Clin Invest 56:905-913, 1975 WN'ellek B, Opferkuch WV: A case of deficiency of the seventh component of complement in man: Biological properties of a C7-deficient serum and description of a C7-inactivating principle. Clin Exp Immunol 19:223-235. 1975 Smith CW. Hollers JC, Dupree E, Goldman AS, Lord RA: A serum inhibitor of leukotaxis in a child with recurrent infections. J Lab Clin Med 79:87-85, 1972 Soriano RB, South MA, Goldman AS: Defect of neutrophil motility in a child with recurrent bacterial infections and disseminated cytomeglovirus infection. J. Pediatr

8.3:951-958, 197.3 47. 'Van Epps DE, Palmer DL. Williams RC Jr: Characterization of serum inhibitors of neutrophil chemotaxis associated with anergy. J Immunol 113:189-200, 1974 48. W'eston WL, Carson BS, Barkin RM. Slater GE: \onoc-te-macrophage function in the newborn. Clin Res 24: 182A, 1976 49. Cates KL, Grady PG, Shapira E, Davis AT: Inhibition of polymorphonuclear leukocvte chemotaxis by serum from a patient with chronic mucocutaneous candidiasis. Unpublished data 50. Altman LC, Snvderman R. Blaese RM: Abnormalities of chemotactic lymphokine synthesis and mononuclear leukocy-te chemotaxis in Wiskott-Aldrich svndrome. J Clin Invest 54:486-493. 1974 51. WNard PA. Bergenberg JL: Defective regulation of inflammatory mediators in Hodgkin's disease: Supernormal levels of chemotactic-factor inactivator. N Engl J Med 290:76-80. 1974 32. Maderazo EG. Ward PA. WN'oronic CL. Kubik J. DeGraff AC Jr: Leukotactic dysfunction in sarcoidosis. Ann Intern Med. 84:414-419. 1976 53. WNard PA. Goralnick S, Bullock VE: Defective leukotaxis in patients with lepromatous leprosy. J Lab Clin Med 87: 1025-1032. 1976 54. DeMeo AN, Andersen BR: Defective chemotaxis associated with a serum inhibitor in cirrhotic patients. N EngI J Med 286:735-740. 1972

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Clinical conditions associated with defective polymorphonuclear leukocyte chemotaxis.

Clinical Conditions Associated With Defective Polymorphonuclear Leukocyte Chemotaxis Paul G. Quie, MD, and K. Lynn Cates, MD Impressive numbers of cl...
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