Noorbibi K. Day

C8 deficiency in a family with xeroderma pigmentosum. Lack of linkage to the HLA region.

Abstract The present study describes a large pedigree (23 members) of a Tunisian family with C8 deficiency and with a high incidence of xeroderma pigmentosum. It is shown in this study that, although the C8 deficiency is transmitted as an autosomal trait (three homozygous and five heterozygous individuals), heterozygote carriers having half-normal levels of C8 functionally and immunochemically, there is no close linkage between the C8-defective chromosome and the HLA antigen. These observations are in contrast to studies of another family described by Petersen et al. (1) and Merritt et al. (2) where the C8-defective gene was closely linked to MHC.

Reduction of circulating immune complexes by calorie restriction in (NZB × NZW) F1 mice

Levels of circulating immune complexes (CIC) by the Raji cell radioimmunoassay were analyzed in sera of (NZB × NZW)F1 (BW) mice at four ages (3, 9, 12, and 18 months) on different levels of total food intake (Purina lab chow and two defined diets at either 20 cal/day or 10 cal/day). In all three groups of animals the CIC levels at 3 months of age were essentially normal irrespective of dietary intake and increased dramatically in sera of mice of both sexes at 6 and 9 months. The highest CIC values were recorded just prior to death at 12 months of age in sera of mice fed Purina lab chow. In contrast, significantly lower CIC values were observed at 12 months of age on the 10-cal intake (P < 0.001). C3 and Ig deposits in the kidney lesions of the mice were strikingly less in those mice fed the 10-cal diet than those fed either of the other two diets. This value was also significantly lower than that of the animals fed 20 cal per day of a defined diet. These findings suggest that diet may influence lifespan of the shortlived autoimmune-prone BW mice by inhibiting the formation and deposition of immune complexes in vital organs.

Inherited Deficiencies of the Complement System

In recent years, studies of genetically determined deficiencies of components of the complement (C) system have begun to yield the same crucial type of information often yielded in the past by other inborn errors of metabolism, e.g., the primary immunodeficiencies as experiments of nature. To date, the deficiencies of the complement system described in man (Tables 1 and 2) are as follows: C1-esterase inhibitor in patients with hereditary angioneurotic edema; Clq in combined immuno-deficiency states; Clr deficiencies associated with infections and a strange vascular disease with lupus-like lesions and chronic glomerulonephritis; C1s with lupus and lupus-like syndrome; C2 with systemic lupus erythematosus, lupus-like syndrome, dermatomyositis, anaphylactoid purpura, increased susceptibility to infections, Hodgkin’s disease, and discoid lupus, and recently in a patient with chronic lymphocytic leukemia and dermatitis herpetiformis; C3 with increased frequency of infections, in particular, of the pulmonary apparatus; C4 with lupus erythematosus; C5 deficiency with membranous glomerulonephritis, vasculitis, arthritis, and propensity to bacterial infections; C5 abnormality with Leiner’s syndrome, recurrent and persistent gram-negative bacterial skin disease and gastroenteritis; C6 in one individual who is apparently healthy at the moment and in another with repeated episodes of meningococcal meningitis; C7 with Raynaud’s phenomenon; C7 inactivator with apparent good health; C8 deficiency with prolonged disseminated gonococcal infection syndrome, and also in three homozygous C8-deficient siblings in a family in which xeroderma pigmentosa is also present.

A study of complement components C3, C5, C6, C7, C8 and C9 in chronic membranoproliferative glomerulonephritis, systemic lupus erythematosus, poststreptococcal nephritis, idiopathic nephrotic syndrome and anaphylactoid purpura

In a comparative study the hemolytic activity of C3, C5, C6, C7, C8, C9 and the C3 proactivator (C3PA) were measured in sera of 22 patients with chronic membrano-proliferative glomerulonephritis (CMPGN), 15 patients with idiopathic nephrotic syndrome, 10 patients with systemic lupus erythematosus, 7 patients with anaphylactoid purpura and 10 patients with acute poststreptococcal nephritis. In CMPGN, C3, C5, C6, C7 and C8 were low in the majority of the patients, whereas C9 and C3PA were depressed only in 21% and 11% of the patients, respectively. By contrast, C3PA and C8 showed striking depressions in idiopathic nephrotic syndrome. In lupus erythematosus, all the C factors, including C3PA were found to be low with the exception of C9, which was normal in 80% of the patients studied. C3, C5, C6 and C7 were found to be depressed in acute glomerulonephritis; C8 and C9 titers were normal. In all patients studied with anaphylactoid purpura, CH50 and C3 titers were elevated markedly.

The Presence of Active C1 (C1-) on Peripheral Human Lymphocytes

Abstract. We have shown that the first component of complement C1 is present in an active form on the surface of washed human peripheral lymphocytes but not on platelets or erythrocytes. This active C1 (C1‐) was detected by its ability to transfer to sensitized cells carrying C4, i.e., EAC4, forming EAC1‐,4. Active C1 was also able to consume C4. Treatment of these lymphocytes with 0.02 m EDTA removed C1. EDTA‐treated lymphocytes were able to bind exogenous purified human C1. Comparative studies with sentized erythrocytes (EA) and EDTA treated lypmhocytes showed that although fewer molecules of exogenous C1 could bind to the EDTA‐treated lymphocytes than to EA, the consumption of C4 by C1‐ bound to lymphocytes was significantly higher than that observed with EAC1‐. When lymphocytes obtained from 2 patients with chronic lymphocytic leukemia and hypocomplementemia were tested, the release of C1, the C4 consumption and the binding of C1‐ to EDTA‐treated cells were highly inefficient.

Complement in Cancer

The concept of immunological surveillance as a major host defense against foreign cells has been used to explain both graft rejection and the recognition and elimination of cancer cells (Thomas, 1959; Burnett, 1970). Simply stated, this theory proposes that lymphocytes possess the ability to recognize and destroy cells of a foreign graft or cancer cells that are recognized as nonself by the host. The rapid development of this area of investigation into cancer immunology was so heavily weighted in the direction of cell-mediated immune reactions as to neglect the role of humoral immune parameters in the host response. Recent experiments have demonstrated that complement can play a limiting role in both graft rejection (Koene et al., 1973) and tumor cell destruction (Old et al., 1967; Kassel et al., 1973). These results emphasize the need to reevaluate our present concepts of tumor immunology. This was done in a recent review by Nishioka (1976), who reiterates the need to take an overview of the entire immune system and the interplay of its component parts in the tumor-host relationship. Nishioka divides the immunological surveillance system into four segments: (1) the classical pathway of the complement system; (2) the C3 shunt or alternate pathway of complement; (3) the cell-mediated immunity (mainly lymphocytes) system; and (4) the immunoglobulin-mediated system. The stress placed on the role of the lymphocyte-mediated system in tumor immunology thus covers only one-fourth of the host defense mechanism, whereas the complement system works synergistically with those segments of the immune system involving immunoglobulins, lymphocytes, macrophages, granulocytes, erythrocytes, and platelets.

Complement and the Major Histocompatibility Systems

Hereditary deficiencies of specific components of the complement (C) system were first discovered in experimental animals (Moore, 1919; Coca, 1920; Hyde, 1923) and later in man (Klemperer et al., 1966). These isolated C deficiencies have been of importance for the understanding of the functional interrelationships between the various C components and in elucidating the biological significance of this complex system. Inherited deficiencies, among other possibilities, may be the outcome of genetically determined defects resulting in any one of the following: (1) total absence of synthesis of one or more of the polypeptides that make up the biologically active component due to the lack of function of either a structural or a regulator gene; (2) the production of a functionally inactive component due to a structural gene defect; or (3) the continuous synthesis or constitutive derepression of a specific inhibitor. Irrespective of which mechanism(s) mentioned is the basis for each specific deficiency, we shall denote genes resulting in deficient C components as C° genes; e.g., C2° is a C2-deficient gene.

Sera from breast cancer patients contain an IgA antibody to a breast cyst fluid component

We have previously demonstrated that aspirated breast cyst fluids from women with benign breast disease contained a particulate component (BCF-PC) that reacted with antiserum to the murine mammary tumor virus (MuMTV). Since women with breast cancer contain antibodies and antigens reactive with MuMTV it was of interest to measure the immune response in breast cancer patients to the BCF-PC. Sera were obtained from breast cancer patients prior to surgery and 5 days postmastectomy, from women with benign breast disease and from healthy women. Analysis for antibody to the BCF-PC was by an enzyme-linked immunosorbent assay. IgA from premastectomy breast cancer patients was significantly more reactive with the BCF-PC than was IgA from women in the other categories (P < 0.001). In contrast, IgG binding to the BCF-PC did not differ among the various groups. It was further demonstrated that the reactivity of IgA from any particular serum for the BCF-PC remained constant for different BCF-PC isolates. Other fractions of breast cyst fluids were unreactive with IgA from breast cancer patients. Determination of serum IgA levels in these women revealed that the mean IgA level was significantly higher in healthy women than in the other categories (P < 0.001). Individual IgA levels and levels of IgA antibody to the BCF-PC were found to be not correlated in breast cancer patients. These results indicate that the production of a specific IgA antibody to the BCF-PC increases in sera of patients with breast cancer. Lastly, it was shown that preincubation of patients sera with disrupted MuMTV, but not intact MuMTV, severely reduced subsequent IgA binding to the BCF-PC. The analysis of sera for IgA antibody to the BCF-PC may be of value for the detection of breast cancer or its recurrence.

Isolated Deficiencies of the Complement System in Experimental Animals

In addition to the genetic deficiencies of complement (C) components in man, genetically transmitted or experimentally induced deficiencies of individual components of the С system have been described in animals of various species (Table 1). These animals provide a useful model for study of the requirement of complement activation by both the classical and alternative pathway for immune reactions and defense mechanisms in vivo and in vitro.