Alexander R. Lawton

Periodic fever syndrome in children.

OBJECTIVES To describe the presentation, clinical course, therapeutic response, and long-term follow-up of patients with a syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA). STUDY DESIGN Patients with PFAPA (n = 94) referred over a 10-year period completed a registry form and provided medical records. Follow-up telephone calls were made in late 1997 to determine the persistence of episodes and sequelae. RESULTS PFAPA episodes lasted 4.8 days (95% confidence interval 4.5 to 5.1) and recurred every 28 days (confidence interval 26 to 30), with a maximal temperature of 40.5 degrees C (confidence interval 40. 4 degrees to 40.6 degrees ). Of the 83 children available for follow-up, 34 no longer had episodes. In the remainder the episodes did not differ in character but recurred less frequently over time. The affected children had no long-term sequelae. Glucocorticoids were highly effective in controlling symptoms. Tonsillectomy and cimetidine treatment were associated with remission in a small number of patients. CONCLUSIONS PFAPA is a not uncommon cause of periodic fever in children. In some children the syndrome resolves, whereas symptoms in others persist. Long-term sequelae do not develop. The syndrome is easily diagnosed when regularly recurring episodes of fever are associated with aphthous stomatitis, pharyngitis, or cervical adenitis.

Syndrome of periodic fever, pharyngitis, and aphthous stomatitis

A syndrome of periodic fever that resembles human cyclic neutropenia in its clinical presentation has been identified in 12 children observed at two major referral centers. Attacks characterized by abrupt onset of fever, malaise, chills, aphthous stomatitis, pharyngitis, headache, and tender cervical adenopathy occur at 4- to 6-week intervals over periods of years. These episodes of illness resolve spontaneously in 4 to 5 days. Mild leukocytosis and elevation of the erythrocyte sedimentation rate during attacks are the only laboratory abnormalities. Affected children grow normally, are not unusually susceptible to infection, and exhibit no long-term sequelae. Attacks may be aborted by short courses of prednisone but do not respond to nonsteroidal anti-inflammatory agents. This syndrome is sporadic and appears to be much more common than cyclic neutropenia.

Effects of Anti-Ig Antibodies on the Development and Differentiation of B Cells

It is now well known that B cells characteristically express immunoglobulin receptors on their surface. On average, each B lymphocyte bears approximately 10̂ immunoglobulin molecules on its outer cell membrane. A relatively small portion of the carboxy terminal end of the immunoglobulin molecule is embedded in the fluid membrane, and the rest of the surface antibody receptor is exposed. Since these receptors for antigen are intimately involved both in antigen triggering of the immune response and in the induction of specific immune tolerance, it is perhaps not surprising that cross-linkage of surface immunoglobulins with divalent ;mti-Ig antibodies may have either positive or negative effects. Our studies of the effects of anti-Ig antibodies have been concerned chiefly with their inhibitory effects on B cells. We have used antibodies specific for immunoglobulin isotype and allotypic determinants to examine different stages in the life history of B cells. These studies, conducted in chickens, mice, rabbits and humans, led directly to demonstration of the existence of an immature IgM* B lymphocyte whose development is easily blocked by cross-linkage of surface IgM molecules and which has the capacity to give rise to B cells which produce other immunoglobulin isotypes. Indirectly these studies led to the identification of a very immature cell type of B lineage in mammals, the so-called pre-B cell, which has the unusual feature of expressing;/ chains only in the cytoplasm, i.e., surface immunogiobulin receptors are lacking. It is during this stage in differentiation that allelic exclusion is expressed and the process of clonal diversity is initiated.

Ontogeny of B-lymphocytes in the human fetus☆☆☆

Abstract Cells bearing membrane-bound immunoglobulins, a marker for B-lymphocytes, have been sought in hematopoietic and lymphoid tissues of 11 human fetuses, aged 9.5–23 weeks. B-lymphocytes with membrane-bound IgM and IgG were found in liver from one of two fetuses aged 9.5 weeks; only IgM-positive cells were found in the other. IgA-positive cells were first detected at 11.5 weeks. By 14.5 weeks, the percentage of cells in spleen and peripheral blood staining for each class of immunoglobulin was within the range found in blood from 10 term infants and 36 normal children and adults. A different fluorescent antibody-staining technique was used to detect immunoglobulin-secreting cells in selected fetuses. No cells with cytoplasmic immunoglobulin were found at 14.5 weeks, a time when B-lymphocytes had reached normal adult proportions in spleen and blood. With one exception, a single IgM-positive cell in an 11-week fetus, such cells were not seen before 15.5 weeks and were rare thereafter. It is concluded that B-lymphocyte development begins at about the same time as T-lymphocyte development. The order of appearance of cells bearing different immunoglobulin classes is probably IgM, IgG, and IgA. The temporal consistency of appearance of these cells suggests that their development is an event of normal differentiation rather than one dependent upon random antigenic stimulation.

Modification of B Lymphocyte Differentiation by Anti-Immunoglobulins

The discovery that in birds and mammals lymphoid cells mediating delayed sensitivity are developmentally and, in part, functionally independent from those involved in antibody production has greatly stimulated research on the cellular aspects of immunity. Recognition that B and T cells are separate populations has led to the definition of morphologic and functional markers for these cell lines. These markers have made it feasible to study the early events of lymphoid differentiation.

Ontogeny of B-lymphocyte differentiation induced by pokeweed mitogen☆

Abstract Pokeweed mitogen (PWM) induces normal adult lymphocytes to divide and differentiate in vitro to cells containing large amounts of cytoplasmic immunoglobulin of the major classes IgM, IgG, and IgA. We have used this assay to study the ontogeny of B-lymphocyte function in humans. The response of lymphocytes from fetuses, newborns, and infants up to 2 months of age is quantitatively deficient with respect to adult cells and also differs qualitatively in being primarily of the IgM class. Whether the differences in response of fetal and adult lymphocytes are due to functional immaturity of B lymphocytes or to development of regulatory T cells is discussed.

Sequential expression of germ line genes in development of immunoglobulin class diversity

Differentiation of B cells occurs in two discontinuous stages. Primary differentiation of stem cells to B lymphocytes in birds occurs exclusively in the lymphoepithelial bursa of Fabricius; the fetal liver may serve this function in mammals. In chickens both the size of the B-lymphocyte pool and the generation of precursors for cells secreting different immunoglobulin classes is controlled by the bursa. The latter process involves the sequential expression of genes coding for heavy chain constant regions in the order mu, gamma, alpha. The second stage of B-cell differentiation is antigen-driven, and involves proliferation and maturation of B lymphocytes to plasma cells. Ontogenetic development of different classes of B lymphocytes in mammals is orderly, independent of exogenous antigens, and occurs in the sequence mu, gamma, alpha. A developmental switch in expression of Ch genes, beginning with mu, has been experimentally verified. We favor the hypothesis that generation of class diversity of B lymphocytes occurs during the antigen-independent first stage of differentiation, and that the genetic switch in Ch gene expression follows the sequence mu leads to gamma leads to alpha, but evidence of these points remains inconclusive.

T-cell-dependent and independent plasma cell differentiation induced by Escherichia coli Lipopolysaccharide in human peripheral blood lymphocytes.

Abstract Responsiveness of human peripheral blood lymphocytes to Escherichia coli lipopolysaccharide was investigated. Reproducible plasma cell development was observed in LPS-stimulated cultures of human PBLs when two criteria were met: (1) crowded culture conditions, and (2) depletion or removal of adherent cell populations. All isotypes were expressed in culture with IgM-plasma cells being predominant. IgG-and IgA-plasma cells were usually first detectable 1–2 days after IgM-producing cells appeared. Cellular requirements for LPS-induced differentiation of human PBLs were examined. A reproducible IgM-plasma cell response could be detected in cultures of B-cell fractions with less than 2% T cells. When T cells were added to B-cell fractions, IgG- and IgA-plasma cells developed and the IgM response was significantly enhanced. Splenic lymphocytes responded to LPS in a similar manner to PBLs. Minimal thymidine incorporation was seen in LPS-treated blood or spleen lymphocyte cultures. LPS may provide a useful complementary system to pokeweed mitogen for stimulating plasma cell development by human peripheral blood lymphocytes.

Detection of human T cells using anti-monkey thymocyte antisera. Tissue distribution and evidence for antigenic heterogeneity

Abstract Six rabbit anti-monkey thymocyte antisera (AMT) were superior reagents to antisera prepared against human thymocytes, thymocyte membranes, and fetal brain with respect to absorption requirements and fluorescence brilliance on human T lymphocytes. The distribution of T cells in adult subjects was defined using fluorescein-labeled AMT absorbed for T-cell specificity. This reagent reacted with 96% of thymocytes, 75% of peripheral blood lymphocytes, 63% of thoracic duct lymphocytes, 40% of splenocytes, 55% of lymphocytes from intraabdominal lymph nodes, and 13% of nucleated cells flushed from bone marrow. T antigens detected by AMT were expressed on virtually all fetal thymocytes and a minority of fetal spleen cells as early as 13 weeks of gestation. By absorbing AMT with a cultured T-cell line (MOLT-4), it was possible to distinguish a subpopulation of T cells displaying antigen(s) not present on MOLT-4. This subpopulation comprised the majority of thymocytes, one-half of peripheral-blood T cells, but only one-third of splenic or lymph-node T cells. A quantitative absorption assay failed to demonstrate cross-reactivity of AMT with antigens in homogenized human brain or a preparation of brain synaptasomes.

Origin, Distribution and Differentiation of IgA-Producing Cells

A large body of experimental data relating to the ontogeny of cells capable of IgA synthesis has been obtained in diverse species over the past few years. In the aggregate, this information suggests that the initial development and distribution of IgA-bearing lymphocytes is relatively thymus- and antigen-independent, whereas normal maturation of B lymphocytes into IgA-secreting plasma cells depends both on antigen stimulation and T cell help. After examining some of the features of these distinct developmental stages of the IgA class of B cells, and their relationship to other classes of B cells, we will raise for discussion the theory that most IgA cells in the intestinal lamina propria are seeded from gut-associated lymphoepithelial tissues (GALT, i.e., Peyer’s patches and the appendix) as a result of selection and stimulation by intestinal antigens which enter the lymphoid follicles via specialized follicle-associated epithelial cells.