Howard B. Dickler

Chronic granulomatous disease. Report on a national registry of 368 patients.

A registry of United States residents with chronic granulomatous disease (CGD) was established in 1993 in order to estimate the minimum incidence of this uncommon primary immunodeficiency disease and characterize its epidemiologic and clinical features. To date, 368 patients have been registered; 259 have the X-linked recessive form of CGD, 81 have 1 of the autosomal recessive forms, and in 28 the mode of inheritance is unknown. The minimum estimate of birth rate is between 1/200,000 and 1/250,000 live births for the period 1980-1989. Pneumonia was the most prevalent infection (79% of patients; Aspergillus most prevalent cause), followed by suppurative adenitis (53% of patients; Staphylococcus most prevalent cause), subcutaneous abscess (42% of patients; Staphylococcus most prevalent cause), liver abscess (27% of patients; Staphylococcus most prevalent cause), osteomyelitis (25% of patients; Serratia most prevalent cause), and sepsis (18% of patients; Salmonella most prevalent cause). Fifteen percent of patients had gastric outlet obstruction, 10% urinary tract obstruction, and 17% colitis/enteritis. Ten percent of X-linked recessive kindreds and 3% of autosomal recessive kindreds had family members with lupus. Eighteen percent of patients either were deceased when registered or died after being registered. The most common causes of death were pneumonia and/or sepsis due to Aspergillus (23 patients) or Burkholderia cepacia (12 patients). Patients with the X-linked recessive form of the disease appear to have a more serious clinical phenotype than patients with the autosomal recessive forms of the disease, based on the fact that they are diagnosed significantly earlier (mean, 3.01 years of age versus 7.81 years of age, respectively), have a significantly higher prevalence of perirectal abscess (17% versus 7%), suppurative adenitis (59% versus 32%), bacteremia/fungemia (21% versus 10%), gastric obstruction (19% versus 5%), and urinary tract obstruction (11% versus 3%), and a higher mortality (21.2% versus 8.6%).

Lymphocyte Receptors for Immunoglobulin

Publisher Summary This chapter discusses lymphocyte receptors for immunoglobulin (Ig). The methods used to detect lymphocyte receptors for Ig vary widely both as the type of complex utilized and the technique for measuring binding. The chapter describes various techniques available. The nature of the lymphocytes that bind complexed Ig are considered with reference to the sensitivity and/or specificity of the various methods. A detailed consideration of lymphoid cell subpopulations, including the criteria for defining B lymphocytes, T lymphocytes, and undefined lymphocyte-like (UL) cells, is presented in the chapter. Any useful Fc receptor assay system should meet certain basic criteria: (1) the percentage of lymphocytes binding Ig should be titratable to a plateau value. This assumes a discontinuous distribution of receptors on different subpopulations. (2) The Fc dependence of binding should be demonstrated. Because the binding of Ig is dependent on the Fc portion of the molecule, this will help ensure that different assays are detecting similar receptors. (3) Cells, other than lymphocytes, that bear Fc receptors should be either identified and excluded from counts or removed from the population being tested. Such cells include monocytes, macrophages, neutrophils, and basophils.

Global Analyses of Human Immune Variation Reveal Baseline Predictors of Postvaccination Responses

A major goal of systems biology is the development of models that accurately predict responses to perturbation. Constructing such models requires the collection of dense measurements of system states, yet transformation of data into predictive constructs remains a challenge. To begin to model human immunity, we analyzed immune parameters in depth both at baseline and in response to influenza vaccination. Peripheral blood mononuclear cell transcriptomes, serum titers, cell subpopulation frequencies, and B cell responses were assessed in 63 individuals before and after vaccination and were used to develop a systematic framework to dissect inter- and intra-individual variation and build predictive models of postvaccination antibody responses. Strikingly, independent of age and pre-existing antibody titers, accurate models could be constructed using pre-perturbation cell populations alone, which were validated using independent baseline time points. Most of the parameters contributing to prediction delineated temporally stable baseline differences across individuals, raising the prospect of immune monitoring before intervention.

Studies of Ia Antigens on Murine Peritoneal Macrophages

Murine peritoneal cells, both induced and noninduced, were examined For Ia antigens by a variety of techniques. Complement‐mediated cytotoxicity and indirect immunofluorescence, analyzed by both visual microscopy and the fluorescence‐activated cell sorter, detected Ia antigens on the surface of an average of 8% to 15% of cells with the morphologic and functional characteristics of macrophages. Internal radioisotope labeling studies showed that these antigens were actually synthesized by the macrophages. The antigens were borne on molecules which consisted of two components with apparent molecular weights of roughly 33,000 and 25,000 daltons. At least some of these molecules existed as a two‐chain structure of 58,000 daltons linked by disulfide bonds. Although macrophage Ia antigens appeared to be structurally similar to the Ia antigens found on spleen cells, the radioisotope labeling studies indicated that the quantity of labeled Ia‐bearing molecules isolated from peritoneal macrophages was at most 1/15 that found for B lymphocytes. In addition, anti‐Ia antisera failed to inhibit the binding of heat‐aggregated immunoglobulin to the Fc receptor of macrophages. Thus, Ia antigens appear to be present at very low levels in macrophage populations, similar to the low levels of Ia antigens found in T‐lymphocyte populations. These studies suggest that Ia antigens exist on only a subpopulation of peritoneal macrophages. Alternatively, all cells in the population might bear small amounts of Ia antigens with only a fraction having sufficient numbers of molecules to be detected by the assay systems used.

Independent ligand occupancy and cross-linking of surface Ig and Fcγ receptors downregulates B-lymphocyte function. evaluation in various B-lymphocyte populations

When two distinct B-lymphocyte membrane receptors (Fc gamma R and sIg) are independently occupied by their respective multivalent ligands, inhibition of the antibody-forming cell response occurs but proliferation is not inhibited. This regulatory signal was examined in various B-lymphocyte populations. Unprimed B lymphocytes from immune deficient CBA/N and autoimmune MRL/l mice were responsive to this regulatory signal. In contrast, unprimed B lymphocytes from autoimmune NZB mice and antigen-primed B lymphocytes from normal DBA/2 mice were not. Together with previous results, these data suggest that resting B lymphocytes which have not encountered antigen are most susceptible to this regulatory signal. Lack of responsiveness to this downregulatory signal may contribute to the hyper-responsiveness of NZB B lymphocytes.

Immunologic tolerance for immune system-mediated diseases.

Induction of long-term, antigen-specific immunologic unresponsiveness holds great promise for the treatment of many immune system-mediated diseases, including asthma, allergies, autoimmune diseases, and transplant rejection. Unlike current immunosuppressive treatments, immunologic tolerance therapies would affect only the undesired immune responses, leaving protective immunity intact. A variety of approaches to immunologic tolerance induction are being taken, reflecting the molecular and cellular complexity of immune system activation and regulation. The presentations summarized in this report represent promising strategies, some of which are being evaluated in advanced animal models and human clinical trials. Approaches presented include the following: interference with costimulatory signals in T-cell induction, T-cell receptor antagonism by altered peptides, exploitation of antigen-induced apoptosis to eliminate undesired T cells, opposition of inflammation by the induction of regulatory cytokines, induction of transplant tolerance by mixed chimerism, and deviation from deleterious allergic antibody responses by use of immunostimulatory DNA sequences. These multifaceted approaches are strongly supported by knowledge of basic immune mechanisms, which should facilitate the rational development of these therapies for controlling immune-mediated diseases.

The Effects of Pharmacol ogic Agents on Immune‐Complex‐induced Redistribution of B‐Lymphocyte Fc Receptors

The effects of pharmacologic agents on the immune‐complex‐induced redistribution of B‐lymphocyte Fc receptors (and, as a control, the anti‐Ig induced redistribution of surface Ig) were examined. Immune‐complex‐induced capping of B‐cell Fc receptors was moderately to markedly inhibited by the combination of colchicine and cytochalasin B, the Ca ++ ionophore A23187, and the local anaesthetic lidocaine but was only slightly inhibited by cytochalasin B alone and was not inhibited by colchicine alone. Inhibition of capping was not due to the inhibition of binding of immune complexes to the B‐lymphocytes or to decreased cell viability since these effects were absent. Preformed immune complex‐Fc receptor caps were disrupted by A23187. lidocaine, and the combination of colchicine and cytochalasin B, but not by either colchicine or cytochalasin B alone. The effects of the pharmacologic agents were similar for Fc receptors and surface Ig in all cases. These results suggest that ligand bound Fc receptors are affected by cytoskeletal structures and that the ligand‐induced redistribution of two distinct B lymphocyte surface receptors (Fc receptors and surface Ig) occurs by similar or identical mechanisms.

The possible role of i region determined cell surface molecules in the regulation of immune responses.

An hypothetical model has been presented by which I region determined cell surface molecules (Ia antigens) mediate the collaboration between T cells and B cells leading to control of the humoral immune response. The model proposes an analogy between Ia antigens and the constant regions of Ig chains. The absolute requirements of this model are: a) On the B cell the Ia antigen is closely associated with the Fc receptor; b) On the T cell the Ia antigen is closely associated with the product of a linked variable region gene which functions as a specific T cell binding site; and c) The interaction between the T cell Ia molecule and its B cell counterpart leads to B cell activation. By the proposed interactive model no additional Ir gene products are required to explain current concepts of Ir gene function. The experimental evidence from our own laboratory and elsewhere upon which this model is based has been reviewed and a variety of consequences and predictions of the model have been examined. There are numerous aspects of the model which, because of a lack of hard data, are open to alternative explanations. The possible usefulness of this model should lie in its ability to suggest further experiments to elucidate the mechanism of B cell activation and control of the immune response.

Human lymphocyte dependent antibody mediated cytotoxicity: Adherence of lymphocytes to antibody treated target cells

Abstract An in vitro human antibody dependent cell mediated cytotoxicity system was used to study the adherence of nonsensitized attacking lymphocytes from peripheral blood to antibody coated melanoma target cells. Specific adherence of attacking cells was documented by labeling the lymphocytes with 51 Cr. The degree of specific adherence was proportional to antibody concentration and incubation time and could be detected before the lysis of target cells. Adsorption of attacking lymphocytes on immune serum treated target cells depleted B cells, enriched T cells, and removed most cytotoxic activity of nonadherent lymphocytes in this system. These results were not found when attacking lymphocytes were adsorbed on normal serum treated target cells.

Genetic linkage between Lym-1, Sas-1 and Mls loci.

Previous studies have demonstrated the existence of two non-H-2 loci which both determine the expression of antigens with characteristics similar to Ia antigens. One locus (Mls) is polymorphic and determines antigens which are stimulatory in mixed lymphocyte cultures (Festenstein 1973). The other locus, which has been provisionally designated LyM-1 (Tonkonogy and Winn 1977), is also polymorphic and it determines antigens which are primarily expressed on B lymphocytes and which are specifically associated with the Fc receptors of these cells (Dickler et al. 1975, Dickler et al. 1977). These two loci (Mls and LyM-1) are very closely linked (Tonkonogy and Winn 1976, Dickler et al. 1977) suggesting that they might represent a second gene complex which is the analogue of the I region of the H-2 complex. The I region of the H-2 complex is closely linked to the S region which determines expression of the alloantigenic serum protein Ss, which is identical to the C4 component of the complement system (reviewed by Shreffler 1976). If the loci LyM-1 and Mls together represent an analogue of the I region of the H-2 complex, it might be expected that they would by closely linked to an Ss-like locus. In this regard, the Sas-1 locus appeared to be a promising possibility. This locus, first described by Wortis (1965) and apparently identical to the Mud-I locus described independently by Naylor and Cinader (1970), controls the expression of an alloantigenic serum protein which has physiochemical and physiological similarities to murine complement components. Moreover, using recombinant inbred strains and the chromosome-1 marker, Dip-l, both Sas-1 and Mls have been mapped to Chromosome 1 (Festenstein et al. 1977, Rosenstreich et al. 1978). However, the relative positions of these linked loci to one another has not been determined. These studies prompted us to examine whether the genes coding for the