Immune Deficiency States Research Articles

Influence of some immune factors on the IL-6 and soluble IL-2 receptors in haemodialysed patients.

In respect to the immune deficiency state of long-term haemodialysed patients, both cytokines and their receptor disturbances have been taken into consideration. The purpose of our study was to evaluate the effect of uraemic and haemodialysis factors on the interleukin-6 and interleukin-2 soluble receptor levels and the reactivity after influenza vaccination. We have found that IL-6 and IL-2 receptor levels were statistically significantly elevated (98.8 +/- 39 pg/ml and 1557 +/- 544 U/ml, respectively) in serum of haemodialysed patients. The fact that increased immune complexes statistically correlated with soluble IL-2 receptor levels (p < 0.01) was very interesting for us. In order to study the immunological response after vaccination, 10 patients have been investigated after influenza vaccination. Plasma samples were collected before, as well as 1 and 4 weeks after vaccine administration. Antibody titres measured by haemagglutinin inhibition showed decreased antibody levels in haemodialysed patients. We conclude that the interleukin disturbance and the elevated interleukin-2 receptor levels together with the presence of circulating immune complexes can influence in some way the immune response of haemodialysed patients.

Surface features of small-intestinal mucosa in childhood diarrheal disorders.

The pathophysiology of diarrhea, especially in the otherwise healthy child, is still poorly understood. The aim of this study was to use the scanning electron microscope (SEM) to examine the surface of the jejunal mucosa of children with chronic nonspecific diarrhea (CNSD) (n = 9) and to compare the findings with specimens obtained from children with (n = 21) and without (n = 11) other gastrointestinal diseases. Light microscopy of the specimens from children with CNSD was normal. However, SEM showed the presence of bacterial colonization with predominantly coccoid organisms in 100% of cases. This colonization was associated with loss of glycocalyx and clumping of the microvilli. The children with celiac disease (n = 9) all showed characteristic appearances with light microscopy, but only one had bacterial colonization on SEM. The surface features of specimens from children with other gastrointestinal disorders (food intolerance, postenteritis syndrome, protracted diarrhea of infancy, and immune deficiency states) were very similar to those from the CNSD group. Bacteria were visible on 89% of specimens, and in half of these cases the organisms were bacilli. SEM of specimens from children with no gastrointestinal disease (ages 11-107 months) suggested an increased density of villi/unit area with advancing age. Bacteria were present in only two cases and did not include bacilli. The findings suggest that bacterial colonization of the surface of the small intestine is common in children with several gastrointestinal diseases and may play a part in their pathogenesis. Routine SEM examination of jejunal biopsies provides information not available from standard light microscopy, which may be relevant to the treatment of children with chronic diarrhea.

Immune deficiency in familial duodenal atresia

The familial occurrence of duodenal atresia is uncommon. This study evaluated the inheritance patterns, the nature and associations, and the presence of immunologic deficits in duodenal atresia recurring in at least three siblings each in two nonrelated families. In the first family, an association with Fanconi's anemia was observed in three of seven pregnancies (2 boys, 1 girl) suggesting an autosomal recessive mode of transmission. Patients died as a result of overwhelming (fungal) septicemia in association with pancytopenia. In a second family, identical multiple atresias occurred in two female siblings born 18 months apart and a third child with a duodenal stenosis. Overwhelming sepsis and a T-cell dysfunction was seen in the postoperative period, which had partially corrected by follow-up at 5 months. A history of family occurrence of duodenal atresia should alert the physician to the possibility of associated pathology including immune deficiency states.

Production of T-helper cell subsets and cytokines by lymphocytes from patients with chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis (CMC) is a heterogeneous group of disorders characterized by recurrent and persistent superficial candidal infections. Cytokine-induced dysregulation of T-helper cell function has been described in other immune-deficient states but has not been studied in CMC patients. We studied T-helper cell subsets by flow cytometry and cytokine production by stimulated lymphocytes in six CMC patients, two healthy pediatric controls, and five healthy adult controls. Peripheral blood lymphocytes were stimulated in vitro with phytohemagglutinin or Candida albicans extract, and the production of interleukin-2R (IL-2R), IL-4, IL-10, and gamma interferon in the supernatants was measured by enzyme-linked immunosorbent assay. CMC patients had a decrease in the CD29+/CD29+ cell population compared with the numbers in controls (P < 0.02). The percentage of CD4+/CD45RA+ cells was greater in patients than in controls, but the difference was not significant. There was no difference in the production of IL-10 or gamma interferon by the patient lymphocytes. CMC patients produced more IL-4 than the controls (P < 0.001), whereas the controls tended to produce more IL-2R than the patients (P = 0.19). These findings support the concept that a decrease in CD4+/CD29+ T-helper inducer cells along with T-helper cell dysregulation may lead to defective memory responses to antigens in CMC patients and a decrease in cell-mediated immunity due to inhibition of TH1 cells by increased levels of IL-4.

Why remove leukocytes from labile blood products in 1995?

During the last 15 years, the techniques to prepare leukocyte-poor cellular blood components greatly improved, as well as our knowledge about the role of leukocytes in many adverse effects of transfusion. These two facts favor the extension of indication of leukocyte-poor blood components. Leukocytes in blood components may be detrimental to their storage, due to their metabolic needs and to their progressive lysis, leading to the release of cytokines. Leukocytes are the exclusive vector in blood of CMV and HTLV viruses. Leukocytes are a key element of the immune modifications induced by transfusion. HLA alloimmunization is favored by the transfusion of large quantities of leukocytes HLA different from the recipient whose immune functions are intact. Conversely, the risk of transfusion associated graft versus host disease is dependent of the transfusion of mature T lymphocytes sharing a partial identity with the recipient, and/or an immune deficient status of the recipient. Between these two extremes, many other effects related to the presence of leukocytes in cellular blood components, as are the transfusion effect observed in transplant recipients, the increased risk for bacterial infection after transfusion, the increased risk for tumor recurrence or the reactivation of virus infections, remain to be fully understood. Despite recent significant improvements, further studies, experimental as well as clinical, will be needed to expand the indications of leukocyte-poor blood components.

Fungal nail disease: a guide to good practice (report of a Working Group of the British Society for Medical Mycology).

#### Summary points The term onychomycosis refers to fungal infection of the nails whether this is a primary event or a secondary infection of a previously diseased or traumatised nail. Infection may be due to dermatophyte (ringworm, tinea unguium), yeast, or other non-dermatophyte (mould) species, and the clinical appearance may indicate the nature of the infecting organism. In paronychia chronic infection of the nail fold is most often caused by Candida species, but bacterial infection with Gram negative species such as Pseudomonas may coexist. Acute paronychia (whitlow) due to staphylococcal infection may also occur, and the presence of these bacterial infections will influence management. Invasion of the nail plate by Candida species may occur in the presence of paronychia, immune deficiency states (including chronic mucocutaneous candidiasis), Raynaud's disease, or endocrine disorders. This paper reviews the clinical features of onychomycosis and the differential diagnosis of nail dystrophy, gives the reasons for appropriate mycological investigation, and discusses guidelines for appropriate treatment on the basis of laboratory findings and particular clinical situations. Treating onychomycoses is difficult but is important because they do not resolve spontaneously. About 30% of all superficial fungal infections affect the nail.1 2 A recent population survey of dermatophyte onychomycosis has suggested a prevalence of 2.8% for men and 2.6% for women in the United Kingdom.3 …

Antibodies to CD40 Prevent Epstein-Barr Virus-Mediated Human B-Cell Lymphomagenesis in Severe Combined Immune Deficient Mice Given Human Peripheral Blood Lymphocytes

CD40 is expressed on both normal and neoplastic B lymphocytes. Signal transduction through CD40 in vitro has been shown to exert stimulatory effects on normal B cells and inhibitory effects on Epstein-Barr virus (EBV)-induced B-cell lymphoma lines and some other cell lines derived from patients with aggressive histology lymphoma. The transfer of normal human peripheral blood lymphocytes (huPBL) from EBV-seropositive donors into severe combined immune deficient (SCID) mice has been previously shown to result in the generation of human B-cell lymphomas. These tumors are similar to the highly aggressive EBV-induced lymphomas that can arise clinically after transplantation or in the setting of immunodeficiency. Treatment of huPBL-SCID chimeric mice with anti-CD40 or anti-CD20 monoclonal antibodies (MoAb) significantly delayed the development of EBV-induced B-cell lymphoma. However, the effects of the two MoAb were mechanistically distinct. Anti-CD40 treatment prevented lymphoma generation, while still allowing for functional human B-cell engraftment in the huPBL-SCID mice compared with mice receiving no treatment, all of which succumbed to lymphoma. By contrast, treatment with anti-CD20 significantly inhibited total human B-cell engraftment in the SCID recipients, which accounted for the absence of lymphomas. In vitro assays examining the transformation of human B cells by EBV also indicated that anti-CD40 could directly inhibit EBV-transformation, whereas anti-CD20 antibodies had no effect. Thus, anti-CD40 exerts selective effects to allow for the engraftment of normal human B cells and prevent the emergence of EBV lymphomas. Stimulation of CD40 by antibodies or its physiologic ligand may, therefore, be of significant clinical use in the prevention of EBV-induced B lymphomas that may arise when EBV-seropositive individuals receive immunosuppressive regimens after transplantation or in immune deficiency states, such as acquired immune deficiency syndrome.

The other immune deficlency—Immunoglobulin disorders

Educational objectives: To know the normal physiology of the immunoglobulins, to recognize immune deficient and hyperimmune states, and to formulate a plan to deal with them.

Bronchiectasis.

Preview A host of congenital and acquired conditions may lead to chronic dilatation of the bronchi, or bronchiectasis. What are the most common clinical signs of the disease? Which diagnostic tests are most helpful in pinpointing the underlying disorder? In this article, Drs Marwah and Sharma address these questions and review treatment options and key elements of prevention.

Specificity and editing by apoptosis of virus-induced cytotoxic T lymphocytes

Recent studies have defined an immunological network by which the acute cytotoxic T-lymphocyte response to viral infection modulates or is modulated by the antigen load and by crossreactive memory T cells. Down regulation of the acute CTL response can be associated with either antigen-dependent or antigen-independent apoptosis, and the host enters a state of immune deficiency as these T cells become sensitized to apoptotic mechanisms.

Moraxella catarrhalis Bacteremia and Preseptal Cellulitis

Invasive disease due to Moraxella catarrhalis is rare and has been associated mostly with immune deficiency conditions. We describe the first case of M catarrhalis bacteremia and preseptal cellulitis in an immunocompetent infant. This organism may be evolving from one with low pathogenicity to one with increased pathogenicity.

Treatment of bacteria-biofilm graft infection by in situ replacement in normal and immune-deficient states

Purpose: Complications of grafts infected with coagulase-negative staphylococci can be eradicated by antibiotic administration, tissue debridement, and in situ graft replacement, but successful treatment may be diminished in a setting of altered immune function.Methods: In a canine model of an established aortic graft infection from Staphylococcus epidermidis, outcomes after in situ replacement were compared between normal dogs and animals made immune-deficient by administration of azathioprine (50 mg/day) and prednisone (10 mg/day). In situ replacement of an infected infrarenal aortic graft with either antibiotic-bonded (silver-ciprofloxacin; Ag-cipro) or conventional polytetrafluoroethylene (PTFE) grafts was performed in 17 control and 18 immune-deficient animals.Results: Four weeks after implantation of a Dacron graft colonized with a biofilm of S. epidermidis, all study animals demonstrated a bacterial biofilm infection with perigraft inflammation or abscess, and in immune-suppressed dogs the incidence of perianastomotic aortitis was increased (p < 0.05). Six weeks after in situ replacement both the Ag-cipro and conventional PTFE grafts were healed without signs of infection in controls, but anatomic evidence of persistent infection and increased S. epidermidis recovery was observed in immune-suppressed animals that underwent in situ replacement of a standard (five of seven) versus antibiotic-bonded (one of 11) PTFE graft (p < 0.006). Overall in situ replacement with an antibiotic-bonded graft yielded a lower frequency of S. epidermidis recovery (two of 19 Ag-cipro graft biofilm with positive culture results versus nine of 16 conventional graft biofilm with positive culture results; (p < 0.003).Conclusions: This study supports the efficacy of in situ replacement for low-grade graft infections caused by S. epidermidis in normal hosts and demonstrates superiority of antibiotic-bonded grafts in immune-deficient hosts.

Treatment of bacteria-biofilm graft infection by in situ replacement in normal and immune-deficient states

Treatment of bacteria-biofilm graft infection by in situ replacement in normal and immune-deficient states

Nutrition, Immunity and Infections: T Lymphocyte Subpopulations in Protein--Energy Malnutrition

Protein energy malnutrition (PEM) is one of the most frequent causes of secondary immune deficiency states. Alterations either in cellular or humoral immune mechanisms increase the susceptibility to infections in the malnourished organism. Infections aggravate the interrelationship of malnutrition to immune deficiency and infections, resulting in future adverse effects of malnutrition on humoral and cellular immune systems, IgG, IgM, IgA, C3, and T lymphocyte subpopulations were identified in 29 patients with PEM and 15 healthy infants serving as the control group, ranging between 3 and 24 months of age. Patients with PEM demonstrated elevated levels of IgG, IgM and IgA when compared to the control group (P < 0.01, P < 0.01, P < 0.01), C3 levels were significantly lower than the values of the control group (P < 0.01).

Reactive arthropathy and autoimmunity in non-HIV-associated immunodeficiency.

The spectrum of arthropathy in non-HIV immune deficiency states includes arthritis due to prevalent infectious pathogens and autoimmunity that may in some instances be triggered by microorganisms. Joint symptoms may be clinical manifestations of disease, or they may develop later during therapy for immunodeficiency. Pathogenesis can be related to occult infection, loss of mucosal barrier function, defective clearance of immune complexes, or aberrant immune responses. Proper treatment includes an appreciation of likely pathogens, an understanding of the nature of immunologic deficits, and rigorous exclusion of immune dysfunction that may be secondary to treatment.

Human herpesvirus type 6: review.

Human herpesvirus type 6 (HHV-6), a newly recognized human herpesvirus first described in 1986, is morphologically similar to other herpesviruses but is distinguishable from all of them by some unique in vitro biological effects, specific antigenic analysis, and patterns of endonuclease restriction digests of DNA. In vitro HHV-6 exhibits tropism mainly for T lymphocytes, but it also infects other cells, including B lymphocytes, monocytes-macrophages, glial cells, and fibroblasts. Because HHV-6 causes frequent infection in infants and children, a seroprevalence rate of antibody to this virus of up to 80% has been reported in the United States. Infection in infancy develops as levels of maternal antibody wane, thus resulting in either subclinical infection or an acute febrile illness termed exanthema subitum. Primary infection acquired later in life causes a disease resembling acute infectious mononucleosis. Since HHV-6 shares the capacity to establish latent infection with other herpesviruses, frequent viral reactivation is probably the explanation for the high incidence of serologically proven active HHV-6 infection found simultaneously with active infection due to other herpesviruses as well as in the presence of various immune deficiency conditions.

Optimum management of the discharging ear.

Discharge from the ear can be the result of many disease processes. The ear may discharge blood, pus, cerebrospinal fluid (CSF) or wax. Keratosis obturans, stenosis of the external meatus and benign tumours of the external meatus all lead to wax build-up, which may cause recurrent attacks of otitis externa. Malignant tumours, such as basal cell carcinoma, squamous cell carcinoma and tumours of ceruminous gland origin may also present with discharge. Tumours should be excluded by submitting all material removed from the external canal for histological examination. Single or multiple abscesses (known as furuncles) may occur in the hair follicles in the skin of the external acoustic meatus (EAM). Compulsive scratching, hearing aids and foreign bodies placed in the ear predispose to otitis externa, which is also often associated with infection by Pseudomonas aeruginosa, Staphylococcus aureus and faecal organisms. Management may be with aluminium acetate 14%, topical antibiotic/steroid drops, a gauze wick soaked with icthammol 10% in glycerin or polymyxin B sulphate--neomycin sulphate--hydrocortisone acetate cream placed into the EAM and replaced every 24 to 48 hours, or systemic antibiotics according to severity. Malignant (necrotising) otitis externa causes progressive destruction of the temporal bone, and cranial nerve palsies (usually facial first). Treatment is limited debridement of infected bone, accompanied by intravenous aminoglycosides, and local antibiotic treatment and aural cleanout or oral ciprofloxacin. Middle ear conditions causing discharge include acute otitis media, infected grommets, traumatic perforations and chronic suppurative otitis media, as well as tumours of the ear canal skin and middle ear, radiation-induced otitis externa and osteoradionecrosis of the temporal bone, tuberculosis, Langerhans cell histiocytosis, spontaneous or post-traumatic CSF leaks, Wegeners granulomatosis and immune deficiency states. Topical application of aminoglycoside antibiotics to the middle ear of laboratory animals such as rats, guinea pigs and chinchillas causes sensorineural hearing loss, an effect rarely seen clinically in humans. If the external acoustic meatus and tympanic membrane are obscured by discharge cotton buds, microsuction equipment or syringing are used to remove it. It is often useful to initiate treatment (usually with topical drops, wicks or an oral antibiotic) with a provisional diagnosis. A full examination and adequate visualisation of the tympanic membrane must eventually be performed, if necessary under anaesthesia, or else serious progressive conditions may be neglected. The most useful initial investigation is a swab sent for bacteriological assessment; other investigations are usually indicated by clinical findings and the provisional diagnosis.

Histopathologic Findings of Duodenal Biopsy Specimens in HIV-infected Patients With and Without Diarrhea and Malabsorption

The significance of the human immunodeficiency virus (HIV) in the small intestinal lamina propria in patients with the acquired immune deficiency syndrome or conditions related to that syndrome who have chronic diarrhea and malabsorption is unclear. To investigate this issue, upper endoscopy (after a 12- to 16-hour fast) with duodenal biopsy and aspirate was performed in 20 HIV-infected seropositive homosexual men referred for diarrhea of more than 8 weeks duration (Group 2) and in 9 HIV-infected homosexual men referred for dysphagia or dyspepsia with no symptoms of malabsorption (Group 1). All biopsy specimens were examined by light microscopy and immunochemical staining with monoclonal antibody against HIV glycoprotein gp41. Electron microscopy was performed in 18 patients in Group 2 and in all patients in Group 1. Immunogold electron microscopy was used as a confirmatory test for identified HIV particles. In addition, D-xylose absorption was measured in all patients after a 25-g dose of D-xylose with measurement of serum D-xylose concentration 1 hour after the dose and measurement of 5-hour urinary D-xylose excretion. Mean serum D-xylose was 35.4 +/- 4.5 mg/dL in Group 1 and 15.8 +/- 2.3 mg/dL in Group 2 (P less than 0.001), whereas mean urine D-xylose was 5.5 +/- 0.6 g in Group 1 and 2.0 +/- 0.4 g in Group 2 (P less than 0.001). Immunoperoxidase for gp41 was positive in 5 (56%) patients in Group 1 and in 12 (60%) patients in Group 2. Lamina propria HIV viral particles were identified by electron microscopy in both patient groups. Viral particles were seen within and adjacent to the cytoplasm of mononuclear cells and were not present in enterocytes or neuroendocrine cells. There were no significant differences in serum or urine D-xylose tests between patients with and without lamina propria HIV. In addition, lipid accumulation in intercellular spaces near the basolateral membrane of adjacent enterocytes was seen in 33% of patients with chronic diarrhea. These findings suggest that lamina propria HIV is not a direct cause of enteropathy in HIV-infected patients and that lymphatic obstruction may be one pathophysiologic mechanism producing this malabsorptive state.

Lymphocyte Subpopulation Number and Function inInfancy

Normal values for percentages of lymphocyte subpopulations and functional responses to mitogen stimulation in infancy are not well established. In the present study, lymphocyte subpopulations were examined in umbilical cord blood samples and in peripheral blood samples drawn before 7 and 24 months of age (mean age 10.4 months) from a healthy population of infants born in Tucson, Arizona. Results indicate significant increases occurred from birth to later infancy in the percentages of total T cells (CD3), T-cell subsets (CD4, CD8) and B cells (CD20). The CD4/CD8 ratio and the functional responses to ConA and PWM mitogens significantly decreased from birth to later infancy. PHA responsiveness did not show a significant change. Results from cross-sectional analyses (n=271) were supported in a smaller longitudinal subset (n=37). There were no detectable ethnic- or gender-related differences in cord blood or samples obtained in later infancy. The normal values established in this study will be useful in studies of immune-system maturation and in the clinical evaluation of newborns, infants, and toddlers suspected of either acquired or congenital immune-deficiency states.

Severe combined immune deficiency presenting with cyclic hematopoiesis

At age 2 months a male infant presented with a cyclic clinical syndrome every 14–21 days that included pharyngeal aphthous ulcers, high fever, lymphadenopathy, pallor, and malaise. Serial blood studies indicated cycling of all blood cell elements, compatible with a diagnosis of cyclic hematopoiesis (CH). He also manifested a progressively severe immune deficiency, not described before in human CH. When first studied at age 5 months, he was hypogammaglobulinaemic with normal B lymphocyte numbers. By 6.5 months, he was agammaglobulinaemic. At age 8 months, he developed severe pneumocystis carinii pneumonia, and studies showed a state of severe combined immune deficiency. The patient received a bone marrow transplant from his HLA-identical sister with no preconditioning therapy. Subsequently, normal immune function developed and the cyclic hematopoiesis resolved. The majority of lymphocytes is of donor origin. Persistence of erythrocytes and neutrophils of recipient origin suggests that the hematopoietic stem cells were not abnormal. We speculate that this patient had a primary deficiency of a differentiation factor affecting maturation of lymphoid and myeloid progenitor cells.