Humoral Deficiency Research Articles

Acute Otitis Media in Children Aged Less Than 2 Years

The management of acute otitis media (AOM) in childhood has evolved considerably during recent years as a result of the new insights provided by publication (in 2004) of the American Academy of Pediatrics and the American Academy of Family Physicians guidelines for the treatment of AOM. The new treatment guidelines establish a clear hierarchy among the various antibacterials used in the treatment of this disease and also the use of an age-stratified approach to AOM by recommending an observation strategy ('watchful waiting') without the use of antibacterials for some groups of patients with AOM. Infants and young children aged <2 years represent a target population characterized by a high incidence of AOM (and in particular of recurrent disease), lack of anatomic and physiologic maturity of airways, age-related immune humoral and cellular deficiencies, the presence of antibacterial-resistant pathogens, and a less efficient response to antibacterial treatment. Presently, the evidence accumulated in the literature is not sufficient to conclude that the role of antibacterials is only minimal in the management of AOM and that the watchful waiting policy is the most appropriate choice for patients aged <2 years with a certain AOM diagnosis. However, adherence to such a policy in patients with an uncertain or questionable AOM diagnosis and/or mild-to-moderate symptoms, in addition to its implementation in patients aged >2 years, could reduce substantially the use of antibacterials in children and play a major role in the strategy of decreasing antibacterial resistance.

Common variable immunodeficiency and the gastrointestinal tract.

Common variable immunodeficiency (CVID) is the second most prevalent primary immunodeficiency disorder but clinically the most important. It causes a wide spectrum of symptoms and signs affecting many systems of the body. CVID is a combination of humoral and cell-mediated deficiency, which explains not only why so many systems are affected but also why standard therapy in the form of intravenous immunoglobulin is not always effective. The gastrointestinal tract is the largest immune organ in the body, and it is therefore expected that this immunodeficiency will affect it in some way. The gastrointestinal manifestations of CVID are variable and tend to mimic known diseases, such as celiac sprue, pernicious anemia, and inflammatory bowel disease, but show significant differences on the microscopic level. Many studies continue to confirm a high prevalence of inflammatory, malignant, and infectious gastrointestinal disorders in patients with CVID. The T-cell-mediated defects of this immunodeficiency disorder are thought to be the cause of the majority of the gastrointestinal disorders in CVID and not the antibody deficiency. Therefore, intravenous immunoglobulin alone may be ineffective. Combination therapy with immunomodulators, such as azathioprine and 6-mercaptopurine, may be needed to treat these gastrointestinal manifestations of CVID.

Immunomodulation and immunodeficiency.

This article briefly reviews the concepts of immunodeficiency and immunomodulation as they relate to selected skin diseases in the dog and cat. Immunodeficiency states are uncommon and may be associated with a subnormal or down-regulated immune system, including humoral deficiencies, such as IgA, and abnormal lymphocyte or neutrophil function. Establishing a causal relationship between a skin disease and presumed immunodeficient state has been difficult due to the rarity of such conditions, and the limited nature of the techniques used to characterise the immune system response. Severe combined immunodeficiency in dogs is a well characterised primary immunodeficiency state involving lymphocytes; retrovirus infection in cats may lead to an acquired immunodeficient state with some association with certain dermatological conditions although it remains unclear that infection is causally linked with disease. Immunomodulation usually implies stimulating the immune system along a beneficial pathway. Such a therapeutic approach may involve a wide variety of agents, for example intravenous immunoglobulin. There are few randomised controlled trials with veterinary patients that unequivocally demonstrate beneficial responses to immunomodulatory agents. Interferons are cytokines of major interest in human and veterinary medicine for their antiviral, anti-tumour and immunomodulatory effects. The advent of veterinary-licensed products containing recombinant interferon may enable demonstration of the efficacy of interferons for conditions such as canine papillomatosis and feline eosinophilic granuloma complex. Canine pyoderma has been treated with a number of presumed immunomodulatory agents with limited success. With more detailed knowledge of the pathogenesis of pyoderma it may be possible to develop efficacious immunomodulators.

Role of antibodies in controlling viral disease: lessons from experiments of nature and gene knockouts.

While the role of antibodies in preventing virus infection and reinfection is unquestionable, their contribution to the resolution of viral disease is much more controversial. When humoral deficiencies, in particular Bruton's X-linked agammaglobulinemia (XLA) ([8][1]), were initially described, it

Tracking immunoglobulin variable-gene expression in HIV infection.

B-cell superantigens (SAgs) interact with normal human nonimmune immunoglobulins (Igs) independently of the light-chain isotype, and activate a large proportion of the B-cell repertoire. Recently, the major envelope protein of human immunodeficiency virus 1 (HIV-1), gp120, was found to exhibit SAg-like properties for B cells with potential pathological consequences for the infected host, including accelerated apoptosis and progressive loss of B cells. This unconventional mode of interaction contrasts with its binding to immunization-induced antibodies, which requires the tertiary structure of the heavy- and light-chain variable regions. Examining the temporal development of V(H)3+ antibodies in HIV-1-infected subjects over a 7-yr period showed that V(H)3+ antibodies specific for the gp120 SAg-binding site are deficient. Quantification of V(H)3+ antibodies, which impart protective responses to infectious agents, in serum samples from HIV-seropositive slow progressors and from patients who progressed to AIDS-related manifestations reveals that paucity in V(H)3+ antibodies is a marker of rapid clinical decline. Remarkably, anti-gp160 V(H)3+ antibodies show a gradual decrease in progressors and vary with time, depending on the viral load. Thus, V(H)3+ antibodies could play an important role in protection, and their underexpression may accelerate disease progression. Investigation of the structural basis of the interaction between human Igs and gp120 shows that the viral gp120 SAg can interact only with a subset of human V(H)3+ Igs. A number of amino acid-positions present primarily in the first and third framework regions of the Ig heavy-chain variable regions correlate with gp120 binding. These residues partially overlap with the Staphylococcus aureus protein A-binding site for V(H)3+ Igs. Overall, these interactions could represent a novel mechanism of humoral deficiency resulting from the capacity of a viral SAg to impact an important subset of the B-cell repertoire and to induce B-cell death by apoptosis.

Immunoglobulin deficiency and determination of pneumococcal antibody titers in patients with therapy-refractory recurrent rhinosinusitis.

We examined 245 patients with chronic rhinosinusitis not responding to prolonged antibiotic treatment and tested each patient for humoral antibody deficiencies. Low immunoglobulin levels were found in 22 patients. Five of them had defects of two or more immunoglobulin isotypes that were diagnosed as common variable immunodeficiency (CVI). Seventeen had an IgG-subclass deficiency. Before and after immunization with pneumococcal vaccine, serotype-specific pneumococcal antibody levels were determined to further evaluate the relevance of the underlying deficiency. Significantly reduced antibody titers of pneumococcal serotypes were found in CVI patients (n = 5), while immunization of 17 patients with IgG-subclass deficiency gave different results. Three of the 17 patients responded poorly to pneumococcal immunization and were prone to a polysaccharide specific immunodeficiency. Patients with CVI or IgG-subclass deficiency failing to produce protective antibody levels in more than five serotypes were chosen for antibiotic and/or immunoglobulin substitution therapy. Since recurrent sinusitis in these patients did not resolve with adequate conservative therapy, endonasal microsurgery was then performed and was seen to be a valuable therapeutic option. Our study suggests that an IgG-subclass deficiency may be the first sign of a basic immunological change, resulting in persisting sinus infections.

Selective antipolysaccharide antibody deficiency associated with peripheral blood CD5+ B-cell predominance

Background: Primary humoral deficiencies vary from complete absence of B cells and/or serum immunoglobulin to lacunar deficits involving specific antibody responses to polysaccharides. Objectives: We compared the B-cell CD5 expression in patients with selective antipolysaccharide antibody deficiencies (SPADs), common variable immunodeficiency (CVID), and IgG subclass deficiency and in normal control subjects. Methods: Five patient populations were evaluated: (1) patients with severe SPAD (no protective serologic postvaccine response to any of 12 polysaccharide antigens tested); (2) patients with intermediate SPAD (diminished response to polysaccharide antigens and adequate response to 1 to 3 of 12 serotypes tested); (3) patients with IgG subclass deficiency; (4) patients with CVID; and (5) age-matched control subjects. Blood was collected from all patients and evaluated by using flow cytometry. Results were compared by using the Student t test. Results: Patients with severe SPAD deficiencies had a marked predominance of CD5+ B cells in the peripheral blood (93% to 97% of total B cells, n = 2). The intermediate SPAD group had a mean CD5+ B-cell percentage that was significantly higher than that of the age-matched control group (87.4%, n = 7, vs 52.5%, n = 20; P = .007). Patients with CVID and IgG subclass deficiency had mean CD5+ B-cell percentages that were similar to those of the age-matched control subjects. Conclusions: Our studies demonstrate that patients with SPAD had a markedly increased percentage of CD5+ B cells in the peripheral blood as compared with age-matched control subjects and patients with other humoral deficiencies. This observation suggests that an association may be present between CD5+ B-cell predominance and SPAD. (J Allergy Clin Immunol 1999;103:637-41.)

Syndrome de Jacobsen, thrombopénie et déficit immunitaire humoral

Clinical features of Jacobsen syndrome include facial dysmorphism, congenital heart defects, digit anomalies and mild to moderate psychomotor retardation. Thrombocytopenia or pancytopenia is observed in one half of patients. Two unrelated children, a 6-month- and a 12-year-old, presented with a moderate thrombocytopenia associated with the clinical features of Jacobsen syndrome. Bone marrow aspirates showed, in both patients, normal cellularity with an increased number of micromegacaryocytes. Chromosome analysis showed a partial deletion of the long arm of chromosome 11. The 12-year-old patient had a history of upper respiratory airways infections with immune humoral deficiency (decreased level of IgA and IgM) which, to our knowledge, has never been reported. Jacobsen syndrome is a cause of inherited thrombocytopenia in children. Humoral immune functions must be explored in patients with a history of repeated infections.

Selective deficit in antibodies specific for the superantigen binding site of gp120 in HIV infection

HIV infection is characterized by accelerated apoptosis and progressive loss of B cells. To see whether these abnormalities are related to the property of gp120 to act as a superantigen for VH3(+) B cells, we probed the temporal development of VH3(+) antibodies in HIV-1-infected subjects over a 7-year period. We found that VH3(+) antibodies specific for the gp120 superantigen binding site are deficient. Since VH3(+) antibodies impart protective responses to infectious agents, we quantified VH3(+) antibodies in serum samples from HIV-seropositive slow progressors and from patients who progressed to AIDS-related manifestations. We found that paucity in VH3(+) antibodies is a marker of rapid clinical decline. Remarkably, anti-gp160 VH3(+) antibodies showed a gradual decrease in progressors and, with time, varied depending on the viral load. We conclude that disease aggravation is associated with a decrease of the magnitude of the humoral response, that VH3(+) antibodies play an important role in protection, and that their underexpression may accelerate disease progression. We propose that vaccine preparations able to trigger VH3(+) antibodies might confer a better protection against HIV infection. This work also represents a novel mechanism of humoral deficiency resulting from the capacity of a viral antigen to affect an important subset of the B cell repertoire and to induce B cell death by apoptosis.

Neonatal sepsis: Pathogenesis and supportive therapy

Bacterial infections remain an important cause of neonatal mortality and morbidity. Pathogenesis of the neonate's predilection to infection are multifactorial. Factors directly attributable to the infant include humoral, phagocytic, and cellular deficiencies. Septic neonates may have reduced neutrophil storage pools that cause profound neutropenia. Both correlate with poor prognosis. Antibiotic administration is mandatory in neonatal sepsis. Supplementary treatments may be useful. Granulocyte transfusions, when available, provide neutrophils, improving the neonate's neutrophil count and neutrophil function. The efficacy of intravenous immunoglobulin (i.v.IG) is questionable because the prophylactic and therapeutic administration of i.v.IG fails to reduce the incidence of bacterial infections or affect the overall survival rate. Hyperimmune preparations seem to be more effective. The administration of granulocyte colony-stimulating factor induces myeloid progenitor proliferation, enhances the neutrophil storage pool, produces neutrophilia, and improves neutrophil function. More extensive, well-designed, and carefully control trials are needed to determine the benefit of supportive therapies for neonatal sepsis.

L'introduction des médicaments en réanimation

Primary immunodeficiencies (PID) represent a heterogeneous group of genetic disorders characterised by poor or absent function in one or more components of the immune system. Humoral or antibody immunodeficiencies are the most common form of PID, of which common variable immunodeficiency (CVID) is the most frequent symptomatic form. CVID is usually characterised by hypogammaglobulinaemia with poor antibody specificity, and an increased susceptibility to infections, autoimmunity and lymphoproliferation. Fewer than 10% of CVID patients have a known monogenic basis. Several chromosomal abnormalities (chromosome 18q-syndrome, monosomy 22, trisomy 8 and trisomy 21) are currently identified as causes of hypogammaglobulinaemia, and can manifest with recurrent infections and mimic CVID.Review of clinical charts and laboratory results of paediatric patients followed in the outpatient clinic of PID with a diagnosis of genetic disease and humoral immunodeficiency.Three patients with different genetic diseases (19p13.3 deletion, a ring 18 chromosome and Kabuki syndrome), were identified. During follow-up, they developed signs and symptoms suggestive of humoral deficiency mimicking CVID, despite which immunoglobulin levels were quantified with considerable delay with respect to symptoms onset, and specific management was subsequently delayed.Patients with genetic abnormalities and recurrent infections should be evaluated for hypogammaglobulinaemia. An early diagnosis of humoral deficiency can allow treatment optimisation to prevent complications and sequelae.

Evidence for an immunodeficiency syndrome related to beta‐haemolytic streptococci in patients with psoriasis

AbstractInfection with beta‐haemolytic streptococci is accepted as one of the triggering factors leading to exacerbation of psoriasis. In a long‐term study lasting nine years (1982–1991) we investigated whether there is any evidence of dysfunction of humoral and cellular immune factors, and what part is played by microbial infection in this connection, with specific reference to streptococcal antigens. 110 patients with chronic psoriasis, either clinically inactive (stage 1) or active with eruptions (stage 2) and 70 healthy controls underwent the following immunologic investigations: streptococcal antibody titres, serum immunoglobulins IgM, IgA, IgG, total serum IgE, complement factors C3, C4, B and T cells, and subpopulations. The findings demonstrate that phases of inactivity are associated with a mechanism described as “Immunologic Regulation”‐activated antibacterial titres and unremarkable findings for humoral and cellular parameters. Eruptions of psoriasis are with phases of humoral and cellular deficiency; antibacterial titres are significantly elevated, serum IgM or IgA or IgG show deficient levels, C3 is activated, C4 is decreased, as are serum IgE and T4:T8 ratio. Shift in T‐cell subpopulations may depend on serum IgE concentration.The question for consideration is whether antigen‐eliminating inflammatory lesions present in immunodeficiency phases trigger the formation of circulating immune complexes. It seems probable that the pathogenicity of these immune complexes is controlled by serum factors and that they are involved in the initiation of keratinocyte hyperproliferation.

Immunoglobulin G, A, and M light chain ratios in some humoral immunological disorders.

The total kappa/lambda immunoglobulin light chain ratio and the kappa/lambda ratios within each of the serum immunoglobulin classes G. A. and M were measured in thirteen patients with humoral immunological disorders. Of those patients, eight had common variable immunodeficiency whereas live patients had other forms of humoral immunological deficiencies. Eleven patients had abnormal antibody response in vivo. All but three of the thirteen patients had clearly abnormal light chain ratios in one or more of the immunoglobulin classes.We conclude that humoral immunological disorders, usually characterized by abnormal heavy chain production and a disturbed antibody response, may frequently have a concomitant abnormal synthesis of the light chains resulting in an abnormal kappa/lambda light chain ratio.

New and controversial uses of intravenous gamma- globulin

During the last few years the use of intravenous immunoglobulin (IVIG) has attracted increasing interest for the treatment of patients who do not have a classical humoral antibody deficiency syndrome. In certain situations this approach has revolutionized medical management, e.g. in immune thrombocytopenia. In other areas, such as in Kawasaki's syndrome, IVIG therapy have been shown to be highly beneficial in preventing long term disease sequelae by some investigators, but the field remains controversial. Conditions under which IVIG therapy has been shown to be of potential benefit are: (1) intractable childhood epilepsy; (2) autoimmune diseases, e.g. myasthenia gravis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, idiopathic neutropenia and aplastic anemia; (3) atopic allergy with IgG subclass deficiency including bronchial asthma; (4) in severe infections in combination therapy with antibiotics and as an antipyretic; (5) in Kawasaki's disease; (6) in multiple myeloma and chronic lymphocytic leukemia. Oral and intraventricular administration of IVIG have also been tried, the former for severe diarrhea and the latter to try to rescue the central nervous system from damage by a pathogen. Carefully controlled clinical trials are needed to establish the efficacy of gamma-globulin therapy in these and other conditions.

The immunocompetence of children with congenital heart disease.

We studied the immunocompetence of 18 children with conotruncal malformations (13 with tetralogy of Fallot, 5 with truncus arteriosus) and 22 children with cardiac shunt lesions. There were reduced total T cell percentages and T helper cells in the conotruncal group but no T cell abnormality in the shunt group. Also, 7 of the 18 cases in the conotruncal group had facial dysmorphism reminiscent of the Di George syndrome. These results suggest that patients with conotruncal malformations fall into the wide spectrum of the Di George syndrome. There was some humoral deficiency in both groups with reduced levels of immunoglobulins IgG and IgA and low levels of complement C3 and C4. The clinical records showed a high frequency of infections. Hospital admissions for these episodes had occurred in 61% of the conotruncal group and 32% of the shunt group. Thus, there is an increased susceptibility to infection in children with congenital heart disease, and the predilection to infection has an immunological basis.

463 CELLULAR IMMUNE RESPONSES TO VARICELLA-ZOSTER (VZ) IN THE AGED

Skin test reactivity and in-vitro lymphocyte stimulation responses to V-Z were examined in a large normal population ranging in age from 6 months to 93 years. Emphasis was on evaluation of specific immune competence of the aged. V-Z antigen was prepared from an infected culture of diploid cells. Positive V-Z skin test reactivity by age was as follows: 0-12 mo.(non-immune) 0%; 1-10 yr.-100%; 10-20 yr.-100%; 20-30 yr.-96%; 30-40 yr.-92%; 40-50 yr.-72%; 50-60 yr.-39%; and 60-100 yr.-9%. Thus, waning of cellular immunity as examined by skin delayed hypersensitivity began at age 40. Skin test responses to phytohemagglutinin (PHA) however, remained positive into the 10th decade. In-vitro lymphocyte stimulation responses to V-Z were usually positive (stimulation index ≥ 2.5) until age 60 after which time levels as observed with non-immune individuals were often demonstrated. These in-vitro results appear more sensitive in discriminating susceptibility to reactivation disease. Similar data were observed in a large group of cancer patients who, at a younger age, have depressed reactivity and likewise represent a high risk group for V-Z infection. Antibody as measured by FAMA (fluorescent antibody to membrane antigen) remained positive into the 9th and 10th decades, especially with a history of reactivation (Zoster) V-Z infection; on the other hand, skin test and in-vitro responses were rarely positive in those individuals. Thus, cellular as contrasted with humoral deficiency may account for a propensity to reactivation of varicella-zoster virus.

Immune-inflammatory response in the human neonate.

This review briefly summarizes the salient points regarding the immune inflammatory status of neonatal host defenses. The neonate can marshal an immune response to most antigens and infectious agents. The data from previous studies in this area suggested that neonates were "immunologically null,' but much of this information was derived from interpretations which failed to take into account the inflammatory response. Humoral and cellular deficiencies of cell movement and, perhaps, ingestion and bactericidal activities probably contribute significantly to the compromised host defense characteristic of this period of life. The interactions of these major areas in enabling the neonate to resist infections are largely unknown. The answers to these compelling research questions should provide directions in the future diagnosis and treatment of neonatal septicemia.

In vitro analysis of humoral immunity in antibody deficiency with normal immunoglobulins

The nature of the humoral immune defects in two unrelated patients with normal serum immunoglobulin and specific antibody deficiency was investigated. Five days after a booster immunization with soluble tetanus toxoid, peripheral blood lymphocyte B cells were assayed for the normal appearance of PWM and T-cell-independent antigen-specific IgG anti-tetanus lymphoblastoid B cells and suppressor T cells for these B cells. Patient 2 was totally unable to generate these B cells while patient 1 generated 10% of the normal tetanus specific B-cell activity. PBL samples were analyzed 21 days after immunization for PWM-dependent B-lymphocyte synthesis of total and anti-tetanus IgG and IgM and total and antigen-specific T-helper and -suppressor lymphocyte activity. Patient 1's B lymphocytes could generate normal amounts of both total and anti-tetanus IgG and IgM. However, his T lymphocytes completely suppressed IgG and anti-tetanus IgG production. Patient 2 also had excess radiation-sensitive T-suppressor cells for total and anti-tetanus IgG and IgM. However, this patient's B cells demonstrated an antigen-specific defect in culture in that they produced total IgG normally but were unable to produce specific anti-tetanus IgG. Thus, even with this small patient sample, the heterogeneity of immune defects established in other humoral deficiency diseases appears to exist in the syndrome of antibody deficiency with normal serum immunoglobulin.

Mechanisms in secondary hypogammaglobulinaemia.

Hypogammaglobulinaemia refers to the low levels of circulating antibodies associated with a decreased gammaglobulin zone on electrophoresis. Since IgG is the predominant immunoglobulin a deficiency of it will most readily affect the gammaglobulin zone. Deficiencies of IgA and IgM will not necessarily result in a visual decrease in the latter. For practical purposes the clinically important states are the low immunoglobulin levels associated with disease. For IgG, severe hypogammaglobulinaemia is defined as a serum level in an adult of less than 2.0 g/l (MRC Working Party, 1969). At this level 70% of patients suffer severe infection (Hobbs, 1968). During the first six months of life infants commonly have levels below 2-0 g/l, so that in this period 1-0 g/l is better taken as the critical level. If the onset occurs before the age of 3 years (during which time children are building up their memory bank of IgG responses) the residual IgG is poorer in quality than in an adult and infection is much more of a problem. In adults the quality can be so good that down to 1.0 g/l there is no obvious infection, but the usually preceding loss of IgA and IgM can predispose to gut disturbances and malabsorption and loss of weight are common. In some cases primary humoral responses may be affected and infection with organisms not previously encountered may occur long before low levels of immunoglobulins are seen. Hypogammaglobulinaemia may be a result of a longer term inhibition of the humoral immune system, which may be preceded in the early stages by failure to mount a primary response. A normal gammaglobulin level does not necessarily exclude specific humoral response deficiencies (Hobbs, 1966; Hobbs, 1969). The immunoglobulin deficiency can arise from a variety of immunological abnormalities, which may be genetically determined or may be secondary to some other condition. Secondary hypogammaglobulinaemia is 10-100 times more common than the primary forms. In this paper we shall consider clinical conditions which give rise to secondary hypogammaglobulinaemia, with particular reference to the mechanisms producing it. These may be considered under five broad headings (Table 1; Hobbs, 1971).

A syndrome associating partial albinism and immunodeficiency

Two unrelated patients with partial albinism, frequent pyogenic infections and acute episodes of fever, neutropenia and thrombocytopenia are described. Their pigmentary dilution was characterized by large clumps of pigments in the hair shafts and an accumulation of melanosomes in melanocytes. Melanocytes had few short dendritic expansions, and keratlnocytes were hypoplgmented. No or few Langerhans' cells were detected in skin by electron microscopy and ATP-ase reactions. This pigmentary dilution, different from all other human albinisms, resembles the unique defect of the mutant dilute (d-d) mouse. Despite the presence of an adequate number of T and B lymphocytes, the patients were hypogammaglobulinemic, deficient in antibody production and incapable of manifesting delayed skin hypersensitivity or of rejecting skin grafts. Their leukocytes did not stimulate normal lymphocytes and could not generate cytotoxic cells during mixed leukocyte reaction. T lymphocytes of one patient were unable to exert a helper effect on the maturation of B lymphocytes into immunoglobulin-containing cells following in vitro stimulation with pokeweed mitogen. This suggests that the humoral deficiency might be secondary to a defect of helper T lymphocytes. Granulocytes did not show any morphologic abnormality, and their bactericidal activity was only moderately reduced. An Increased number of polymorphonuclear leukocytes with polar distribution of Concanavaline A (Con A) receptors (capping) was found in one patient and her parents. The family histories suggest that this syndrome is transmitted as an autosomal recessive character.