Selective effects of cyclophosphamide therapy on activation, proliferation, and differentiation of human B cells.

The immune function of B lymphocytes from 12 patients with nonneoplastic immune-mediated diseases receiving chronic low-dose (2 mg/kg per d) cyclophosphamide (CY) was evaluated. There was a selective and differential suppressive effect of CY therapy on the various stages of the B cell cycle including activation, proliferation, and differentiation. The proliferative responses to Staphylococcus aureus Cowan strain I (SAC) and mitogenic concentrations of anti-mu were suppressed. In contrast, B cells that have been presumably activated in vivo proliferated with a normal pattern when exposed to B cell growth factor in vitro. Chronic low-dose CY therapy also suppressed B cell differentiation. Secretion of immunoglobulin by B cells following in vitro triggering with SAC and a T cell supernatant was suppressed in CY-treated patients. Moreover, differentiation of the large in vivo-activated B cells (which do not require an in vitro activation signal) in the presence of appropriate T lymphocyte supernatant was also suppressed. This selective suppression of B cell function at multiple points in the B cell cycle may be responsible for the efficacy of CY therapy in certain antibody and immune complex-mediated diseases.

Effects of in vitro corticosteroids on B cell activation, proliferation, and differentiation.

The present study demonstrates the graded effect of in vitro corticosteroids (CSs) on the different phases of B cell activation, proliferation, and differentiation. Early events such as activation and proliferation of high-dose anti-mu or Staphylococcus aureus-stimulated B cells are profoundly suppressed by the presence of in vitro CSs. The suppressed proliferative response may be mediated by a direct effect on B cells and/or modulation of accessory cell function. Later events in the B cell cycle such as the proliferative response to B cell growth factor after either in vivo or in vitro activation are less sensitive to the suppressive effects of in vitro CSs. The final events in the B cell cycle; namely, the differentiation to the immunoglobulin-producing state, is not suppressed by in vitro CSs. Indeed, depending on the systems employed, there is either no effect or enhancement of immunoglobulin secretion by the presence of in vitro CSs. The graded effect of in vitro CSs on the discrete phases of the B cell activation, proliferation, and differentiation cycle provide new insights into the complex nature of CS-induced modulation of human B cell responses.

In vitro antigen-induced antibody responses to hepatitis B surface antigen in man. Kinetic and cellular requirements.

In this report we define the parameters of the human immune response after immunization with hepatitis B vaccine. 2 wk after booster immunization, there is significant spontaneous secretion of antibody to hepatitis B surface antigen (anti-HBs IgG), which is not further augmented by stimulation with antigen or pokeweed mitogen (PWM). By 4 wk there is little spontaneous secretion of specific antibody, and low doses of antigen or PWM produce significant increases in the amount of anti-HBs IgG produced. By 8 wk the peripheral blood mononuclear cells are refractory to stimulation by antigen, but anti-HBs IgG is produced in response to PWM. 0.5 yr or more after the last immunization, some individuals will manifest an antigen-induced specific antibody response. This induction of anti-HBs IgG by hepatitis B surface antigen (HBsAg) is monocyte- and T cell-dependent. Note that there is a dichotomy in the T cell response to HBsAg. The specific antibody response is clearly T cell dependent, but no in vitro T cell proliferative response to HBsAG could be demonstrated in the immunized individuals. Although the precise reason for the absent proliferative response to HBsAg despite well-established humoral immunity has not been determined, there was no evidence to suggest nonspecific suppression by HBsAg or the presence of an adherent suppressor cell population. The ability to evaluate antigen-induced, antigen-specific responses to HBsAg will be useful in defining the unique interaction between the human immune response and this clinically important viral agent.

Hypocomplementemic urticarial vasculitis syndrome. Clinical and serologic findings in 18 patients.

We identify and describe clinical findings in hypocomplementemic urticarial vasculitis syndrome (HUVS), an uncommon to rare illness related to systemic lupus erythematosus (SLE). A patient with recurrent, idiopathic urticaria-like lesions was diagnosed as having HUVS if a lesional biopsy showed leukocytoclastic vasculitis, the serum C1q was markedly decreased, and antibody to C1q was detected in the patient's serum. The clinical characteristics, serologic findings, and outcome of patients who met these criteria were determined from prospective and retrospective data, including hospital and office records, patient interviews, previously banked serum samples, and freshly drawn sera. Eighteen patients with HUVS were identified, and high incidences of angioedema, ocular inflammation, glomerulonephritis, and obstructive pulmonary disease were found. Renal and lung biopsies showed mesangial or membranoproliferative glomerulonephritis and severe pulmonary emphysema without vasculitis. Pulmonary function was measured in 17 patients, 11 of whom had dyspnea. All dyspneic patients had moderate to severe airflow obstruction, which progressed in all 11 and subsequently improved in only 1. Six of these 11 patients died of respiratory failure, 1 underwent lung transplantation, and 3 of the remaining 4 have moderately severe to life-threatening respiratory insufficiency. Treatment did not appear to alter the progression of obstructive lung disease. In contrast, renal insufficiency improved with treatment in 2 of 2 patients. Angioedema, ocular inflammation, obstructive lung disease, and glomerulonephritis appear to be common in HUVS, and lung disease causes substantial morbidity and mortality. The pathogenesis of HUVS may involve humoral autoimmunity, although it is not clear how autoimmunity would participate in development of obstructive lung disease. Cigarette smoking appears to be a risk factor for fatal lung disease in HUVS. All patients with HUVS should be made aware of this possibility and should be advised, encouraged, and helped to avoid tobacco smoke.

Sterile splenic abscesses in systemic Weber-Christian disease. Unique source of abdominal pain.

A patient with Weber-Christian disease and relapsing abdominal pain due to sterile splenic abscesses is presented. Histologically, acute and chronic inflammation with focal suppurative infiltrates of phagocytosed fat was detected in the absence of vascular or embolic disease, infection, or other apparent cause. Abdominal discomfort, an uncommon manifestation of Weber-Christian disease, usually is related to mesenteric panniculitis. Sterile splenic abscesses represent a previously undescribed complication of Weber-Christian disease, and another source of abdominal pain in this disorder. Although the precise pathophysiology of sterile splenic abscess formation in Weber-Christian disease is unknown, splenectomy is an effective means of alleviating pain.

Herpes zoster in patients with treated Wegener's granulomatosis. A possible role for cyclophosphamide.

In review of the ongoing protocol for the treatment of Wegener's granulomatosis with cyclophosphamide at te National Institutes of Health, an increased incidence of herpes zoster infection was noted. There were a total of nine episodes in seven of a total of 65 patients with a 255 patient year follow-up. The infections occurred while the patients were in complete clinical remission during immunosuppressive therapy. Cutaneous dissemination was noted in two episodes, but no visceral or central nervous system involvement was noted despite continuation of immunosuppressive therapy. The major causal factor of the increased incidence of herpes zoster appeared to be the cyclophosphamide therapy.

Successful treatment with acyclovir of an immunodeficient patient infected simultaneously with multiple herpesviruses.

A patient with recurrent simultaneous chronic infections, including cytomegalovirus pneumonia, disseminated zoster and perineal herpes simplex infection, whose immune responses were deficient (immunodeficient), is presented. Following treatment with acyclovir (19-(2-hydroxyethoxymethyl)guanine), this patient had a rapid remission of these viral infections. The patient's clinical improvement is remarkable considering the duration of the viral infections and the continued immune deficiency. Acyclovir appears to act by a highly selective activation by and inhibition of viral enzymes. Prospective trials of this agent in immunosuppressed patients with herpes virus infections seem warranted.

Isolated angiitis of the central nervous system. Prospective diagnostic and therapeutic experience.

Isolated angiitis of the central nervous system is an uncommon clinicopathologic entity characterized by vasculitis restricted to the vessels of the central nervous system without other apparent systemic vasculitis. Experience with the diagnosis, treatment, and follow-up evaluation in four patients with this disease is presented. Early manifestations of disease include severe headaches, altered mental function, and focal neurologic deficits. The pattern of progression from headaches and altered mental status to multifocal neurologic deficits is particularly suggestive of the diagnosis of vasculitis of the central nervous system. Systemic symptoms such as fever, myalgia, arthralgia, and arthritis, which occur frequently in other vasculitic syndromes, are generally not present in patients with isolated angiitis of the central nervous system. No single laboratory study can firmly establish or completely exclude the diagnosis; consequently, tissue diagnosis with biopsy of the brain parenchyma and leptomeninges may be required. In two patients, recurrent disease developed despite treatment with corticosteroids alone. Sustained clinical remission was induced in all four patients with a regimen of daily cyclophosphamide and alternate-day prednisone therapy. Cyclophosphamide and alternate-day prednisone therapy are considered the treatment of choice in severe, progressive, or corticosteroid-resistant isolated angiitis of the central nervous system.

An unusual case of central nervous system vasculitis.

A patient with CNS vasculitis limited to small vessels is described. Initial spinal cord involvement with paraparesis was followed by multifocal cerebral and cerebellar involvement, depicted by magnetic resonance imaging (MRI). She also had recurrent cerebral bleeding. A diagnosis of vasculitis was made by cerebral biopsy. Immunosuppressive therapy resulted in clinical improvement and resolution of the MRI abnormalities.

Facial erysipelas in the immunocompromised host. Report of two cases.

Two cases of facial erysipelas in immunologically altered hosts are reported herein. The unusual presentation with absence of erythema in the skin lesion is emphasized. Atypical fever patterns were also noted. In one patient, the facial lesion followed the onset of fever by 48 hours, and, in the other, the facial swelling preceded the fever. Various aspects of the patient's altered host status are discussed in light of the atypical clinical presentation. Recognition of facial erysipelas as a potential source of group A beta-hemolytic streptococcemia in immune-altered hosts is important to ensure rapid and appropriate therapeutic intervention.

Primary empty sella syndrome with panhypopituitarism, diabetes insipidus, and visual field defects.

A 58 year old woman with a history of hypothyroidism was evaluated for marked visual impairment and found to have the primary empty sella syndrome with multiple endocrine abnormalities. Visual field determination revealed preservation of vision only in the left inferior quadrants bilaterally. Failure of growth hormone (hGH), cortisol and prolactin to respond to insulin induced hypoglycaemia (0.1 U/kg), of luteinizing hormone (LH) and follicle stimulating hormone (FSH) to respond to gonadotrophin releasing hormone (GnRH, 100 microgram) and of thyrotrophin (TSH) and prolactin to increase after thyrotrophin releasing hormone (TRH, 500 microgram), confirmed the diagnosis of panhypopituitarism. Following water deprivation with a 9% loss in body weight, her urine osmolality remained at 204 mOsm./kg H2O), indicating that she had posterior pituitary deficiency as well. During surgical exploration, which was performed in an effort to improve her markedly impaired vision, a compromised vascular supply to the left optic nerve and chronic arachnoiditis was demonstrated. This case represents one extreme of functional impairment in a syndrome which is generally considered benign and which rarely requires therapeutic intervention. Our patient is compared to 29 reported cases of the primary empty sella syndrome with visual field defects. The operative findings in eight of these cases are reviewed. The need for a multidisciplinary approach and close follow-up of patients with an empty sella and functional deficits is emphasized. Surgical intervention including lysis of adhesions and chiasmapexy has been effective in selected cases in reversing or stabilizing visual field abnormalities.

Corticosteroid-mediated immunoregulation in man.

Glucocorticoids have profound and complex effects on the human immune response. However, the precise mechanisms of the corticosteroid-induced immunoregulation in man have not been precisely defined. Intracytoplasmic corticosteroid-specific receptors appear to be an important common pathway for steroid-induced changes, but variations of receptor parameters do not account for the multifaceted effects on the immune system. Human circulating mononuclear cells redistribute out of the intravascular compartment following treatment with corticosteroids. Although certain components at this redistribution phenomenon have been well-characterized, the importance of this compartmental cellular shift with respect to the mechanisms of corticosteroid-induced immunoregulation are less well-defined. Recent observations that activated lymphocytes may be sensitive to the lytic effects of glucocorticoids suggest that under certain situations the elimination of selected subsets of cells may be a relevant mechanism of corticosteroid-mediated immunoregulation in man. Corticosteroid-mediated effects on monocyte function may be an important mechanism of drug-induced immunoregulation in monocyte-dependent responses. In some experimental conditions, corticosteroids inhibit Interleukin 1 production by monocytes. The immunoregulatory effects of corticosteroids on lymphocyte immune responses are complex. In vitro corticosteroids appear to selectively affect early immunoregulatory events as opposed to altering an established response. Multiple sites of steroid-induced modulations of human B cell responses have been defined.

Cutaneous vasculitis.

Cutaneous vasculitis and vasculopathic processes continue to be difficult to define, diagnose, and treat. Historically, the complexity of these disorders has been compounded by imprecision in terminology and classification and the presence or absence of underlying systemic illness. Approaching the literature with consistent diagnostic constraints and accepted terminology can, it is hoped, eliminate some of the ambiguity. During the past year, several case reports and brief communications regarding cutaneous vasculitis or vasculopathies have appeared, as well as thoughtful basic science reports whose authors have attempted to further the understanding of the underlying pathophysiology. Recent technologic advances have produced recombinant cytokines, growth factors, and thrombolytics that have been used therapeutically for a variety of medical illnesses. The role of these agents in the treatment of cutaneous vasculitis and vasculopathies has varied from provocative in some to therapeutic in others. A number of these reports are discussed.

High dose methylprednisolone for retroorbital Wegener's granulomatosis.

Wegener's granulomatosis (WG) is frequently associated with retroorbital involvement, which typically responds slowly to the standard therapy of oral corticosteroids and cytotoxic agents. We describe the case of a 61-year-old man with WG, who developed marked retroorbital granulomatous inflammatory tissue and experienced a dramatic clinical and radiographic response to the administration of high dose intravenous (iv) methylprednisolone. We believe that high dose iv methylprednisolone may have distinct advantages over standard therapies in the treatment of retroorbital WG.

Neurological complications of vasculitis.

The vasculitides are a group of disorders that include the polyarteritis nodosa group of systemic necrotizing vasculitides, hypersensitivity vasculitis, Wegener's granulomatosis, lymphomatoid granulomatosis, giant cell arteritis, Behçet's disease, and isolated angiitis of the central nervous system. Classification is based on clinical, angiographic, and histological features. The frequency and distribution of neurological involvement vary with the underlying disorder and may provide the initial symptoms. Polyarteritis nodosa and Wegener's granulomatosis may affect both the central and peripheral nervous systems, whereas isolated angiitis of the central nervous system and Behçet's disease affect the central nervous system alone. Neurological dysfunction occurs in 80% of patients with polyarteritis nodosa and fewer than 10% of patients with hypersensitivity vasculitis. The mechanism of neurological dysfunction in the vasculitides is tissue ischemia. The clinical effects of ischemia vary, and symptoms may be transient or prolonged. Mononeuritis multiplex, polyneuropathy, and stroke are frequent complications, but encephalopathies, cranial neuropathies, and brachial plexopathies are seen as well. The occurrence of symptoms late in the course of a disease suggests ischemia resulting from healed, scarred vessels as well as from those that are acutely inflamed; this is the case in Takayasu's arteritis and possibly also in polyarteritis nodosa. Treatment is based on identifying and removing the sensitizing agent when possible. Wegener's granulomatosis requires therapy with cyclophosphamide; temporal arteritis, with corticosteroids. In other vasculitides a balance must be reached between the progression of the disease and the side effects of immunosuppression.

Corticosteroid-induced modulation of immunoglobulin secretion by human B lymphocytes: potentiation of background mitogenic signals.

The modulation of immunoglobulin (Ig) secretion of human peripheral blood mononuclear cells by in vitro hydrocortisone (HC) was evaluated. A marked enhancement of Ig secretion was observed in unstimulated cultures in the presence of HC as compared to cultures without HC. The augmented response was not due to a direct induction of Ig secretion by HC, but resulted from an enhancement or unveiling of the background mitogenic signal provided by the supplemental serum used in culture. HC-induced augmentation of Ig secretion was only seen in unstimulated cultures performed in fetal calf serum (FCS) which is known to possess mitogenic properties. In contrast, HC had no significant effect on Ig secretion of cultures performed in human serum, which provides little or no background mitogenic signal. On the other hand, no enhancement of Ig secretion by HC was seen in cultures maximally stimulated with pokeweed mitogen regardless of whether FCS or human A serum was used. The mechanisms of this modulation of Ig secretion are unclear at present and may include a synergy between corticosteroids and background mitogenic signals (such as FCS) indirectly triggering B cells and/or the dampening of a negative immunoregulatory effect of an accessory cell.