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March 1985, Volume 35, Issue 3

Special Communication

Immuno deficiency

D. Geraint James  ( Royal Northern Hospital, London N 7. )

Immunodeficiency
The world is now faced with the managernent of patients who are immunodefIcient because of several different factors which contribute to a poor soil or terrain (Table 1).Let us study these factors which are responsible for poor resistance against disease.
Factors Influencing the Terrain (Table I)
1) Cellular and Humoral Immunity.
An antigen that penetrates the body’s external defences (skin, mucous membranes, cilia) will encounter two populations of circulating lymphocytes. These two systems, responsible for cellular and for circulating immunity, are the cornerstones of an elaborate and powerful defence system.
T-cells are responsible for cellular immunity. They carry memory, can affect B-cells, reject grafts, recognise cancer, and prevent viral and fungal infections. Their chemical mediators are lymphokines and interleukins and they are involved in the production of interferons. T-cells are particularly involved in the defence against organisms that have an intracellular phase, for instance viruses, mycobacteria, Brucella, and fungi. There are now simplified techniques for recognising T cells and their subsets, and HLA-DR antigen in peripheral blood smears by immunoalkaline phosphatase staining. This lends itself to mass screening of circulating lymphocyte sub-populations, as, for example, in blood donors.1
B-cells are responsible for humoral immunity. They produce five major immunoglobulins and a variety of circulating antibodies. These are responsible for the lysis of antigen by fixing complement, opsonization of bacteria and the neutralization of their products. Deficiencies of B-cells cause increased susceptibility to infection by common bacteria.
Phagocytosis
Phagocytes reach the site of invasion by chemotaxis where they ingest and kill the foreign organism. Impairment of function includes poor chemotaxis, intrinsic cellular defects, abnormal opsonization and neutropenia.


Chemotaxis:can be visualized by several in vitro techniques. Poor leucocyte be locomotion may associated with inhibitors, and blocking factors, deficiencies in complement.
Intrinsic cellular defects may render phagocytes important as in the chronic granulomatous disease of childhood.
Opsonization involves the preparation of bacteria for digestion by phagocytes through the coating of bacteria by the third component of complement (C3b). Opsonic activity requires intact receptor sites, and neutrophil attachment to the organism occurs at the Fab site. Patients with various types of C3b deficiency have poor opsonic activity and are more prone to infections.
Neuz’ropenia may be the result of a variety of causes amongst which are drugs, neoplasia, infections, connective tissue diseases and bypersplenism (Table II).


HLA Antigens
The human leucocyte system of antigens are on the membrane of all nucleated cells and platelets and are inherited on a pair of autosomal chromosomes. Four HLA antigens are found in any individual, two derived from each of two closely linked genetic loci. These tissue antigens are a most important constituent of the terrain and there is now increasing recognition of associations between particular HLA antigens and diseases, some of which are highly significant. Examples include the possession of HLA B27 predisposing the individual to sero-negative arthritis and joint complications of inflammatory bowel disease, and possession of DRw3 which increases the likelihood of, amongst others, some ‘autoim mune disorders’ including thyroiditis, Addison’s disease, and gluten-sensitive enteropathy (Table III).


Other factors influencing the terrain
Malnutrition, ischaemia, disseminated neoplasia, drugs and chemotherapy may all profoundly alter the soil and contribute to the poor resistance of the patient. Splenectomy may lead to increased susceptibility of the individval to certain infections, particularly, pneumococcal and streptococcal (Table IV).


The patterns of opportunistic infections depend upon the mechanism of immunosuppression: thus, patients who have received organ transplants and subsequent immunosuppression may have poor cell-mediated immunity and be at risk of contracting Cytomegalovirus, pneumocystis, and disseminated Candida infections.2 Those who have reduced humoral defence (e.g. Leukaemia patients) may be prone to Aspergillus, pseudomonas, Mycoplasma, and Salmonella infections, whilst those with poor macrophage function (e.g cystic fibrosis) may be especially liable to Staphylococcus and Pseudomonas infection.
Disorders With a Poor Terrain
Acquired Immuno-Deficiency Syndrome (AIDS)
This epidemic disorder is most commonly seen in promiscuous male homosexuals, haemophiliac, and drug addicts with poor cellular immunity. Numerous opportunistic infections are associated with weight loss, fever, diarrhoea, peripheral lymphadenopathy, lymphopenia, and Kaposi’s sarcoma (Table V).

There is an overall mortality of 70% and treatments have all been uniformly unsuccessful. There may be a genetic predisposition because an increased frequency of HLA-DR5 allotype has been noted in male homosexuals with the epidemic form of Kaposi’s sarcoma.3
The immunologic pattern comprises 1-helper cell lymphopenia, an OKT4:OKT8 ratio reduced to less than unity, cutaneous anergy, decreased natural killer (Nt) cells, decreased response to proliferative mitogens (phytohaemagglutinin, Concanavalin A, pokeweed), normal neutrophil function, and normal or increased levels of immunoglobulins. Many patients have an unusual acid-labile form of human leucocyte or alpha-interferon4 and thymosin 1 serum levels may also be high.5 It is hoped that HTLV III antibodies prove to be serological markers of the disease.
Kaposi's Sarcoma
Kaposi’s sarcoma is a multifocal reticuloendothelial neoplasm which has attracted considerable attention in the last decade because of its high incidence in renal transplant recipients, immunosuppressed individuals and sick homosexuals. Kaposi6 originally described pea-sized brownish-red to bluish-red skin nodules that first appeared on the soles and dorsum of the feet and later spread to the rest of the skin and ulti­mately to the gut, liver, and upper respiratory tract. His patients died within three years.
Homosexuals who engage in ano-genital intercourse with numerous partners have eleven times the risk of developing Kaposi’s sarcoma than less promiscuous homosexuals. It occurs particularly in the passive partner receiving semen into the gastro-intestinal tract by rectum or by swallowing it. This suggests that an infectious agent in semen is transmitted or that semen ejaculated into a foreign environment causes an immunologic disturbance. About one half of patients with Kaposi’s sarcoma belong to HLA-DR5 (normally only present in 25% of the population) and these patients have a particularly low level of T4 lymphocytes with a very low T4:T8 ratio, even below 0.5.
The immunological abnormalities found in the blood of such patients extend into the lymph nodes7  T-suppressor cells invade the follicles of the node where they are normally absent and numbers of T helper cells are decreased. There is reduction of the T4:T8 ratio to less than unity. In addition there is B cell hyperplasia within the node and an increase in the number of fully differentiated B cells in the peripheral blood. The latter occur at the expense of the precursors and such polyclonal stimulation would be in keeping with, viral B cell activation in the absence of normal regulatory T cell influence.
The Cause of AIDS? 8-15
French workers isolated lymphadenopathy associated virus (LAV) from a homosexual with pre-AIDS, and also found the same virus in fully-developed AIDS. This was soon followed by a report from the National Institutes of Health. Bethesda, of the isolation of a human T leukaemia retrovirus (HTLVIII) from 48 AIDS patients but from none of 115 healthy controls. The French LAV and American HTLVIII are probably the same retrovirus, which has a selective tropism for T-helper cells. It is likely that there are several co-factors including, of course, T helper cell ablation, B cell overactivity, CMV irnmunosup. pression, genetic HLA susceptibility, and semen (Fig. 1).

IgG antibodies to LAY were found in 75% of patients with AIDS, 90% with lyrnphadenopathy syndrome, 18% of homosexual men without lymphadenopathy and 0.3% of unselective blood donors. The presence of HTLV-III serum antibodies is most strongly associated with sexual exposure to men in the United States and to anai receptive intercourse.
Toxoplasmosis16
Acute toxoplasma encephatitis is difficult to diagnose if it is not suspected, and particularly
so when toxoplasma 1gM antibodies are not detected or when there is no rise in dye-test titres.
It is recognised in homosexuals, drug addicts and in Haitians, but it also occurs in otherwise healthy individuals, who develop immunodeficiency,unaccountably due to ablation of the helper T cell subset. There is a profound lymphopenia, and spinal fluid examination may reveal high protein and low glucose levels.


Pnewnococcal Bacteraemia17
This is associated with pre-existing diseases:-
(a) Disorders of the respiratory system, in- clu ding heavy smoking, steroid-treated asthma, chronic bronchitis, recurrent pneuni onia and cardiovascular disease.
(b) Disorders of metabolism, including chronic renal failure, alcoholism, hypothyroidism, diabetes and   amyloidosis.
(c) Defective immunity. Background factors include splenectomy, leukaemia, myeloma, sickle-cell disease, thalassaemia, systemic lupus and nephrotic syndrome.
Pneumococcal bacteraernia in children is non-pulmonary, and has a case fatality of 13 per cent. It is associated with otitis media, menin-gitis or an upper respiratory infection. The pneumococcus is often found in saliva. The splenectornised child is particularly prone to pneumococcal septicaemia
In the adult, pneumococcal bacteraemia has a case fatality rate of 34 per cent. It occurs particularly in elderly men with pneumonia, some of whom were splenectomised.
Improving the soil
How can we improve the resistance of the immunosuppressed against disease? There are, of course, the obvious factors such as the correction of malnutrition and ischaemia, antibiotics and, where possible, the correction of the underlying disease.
Are there any methods of inimunomanipulation of the soil? We have used transfer factor and levamisole without much benefit. Marrow and thymus transplants may help to overcome poor cellular immunity due to T cell disorders. Like-wise, impaired humoral immunity is being improved by intramuscular and intravenous inimunoglobulins and by plasmapherisis. The future holds promise with the interferons, interleukin-2, monoclonal antibodies, and the use of patching genes (by the technique of recombinant DNA) to provide vaccination against disease (Table VI).


Splenectomy18
Needless splenectomy is deplorable for it may lead to fulminant infections in childhood. Splenectomised children should have polyvalent vaccines and prophylactic penicillin for at least two years. There is also an increased risk in adults, but this is less evident.

References

1. Erber, W.N., Pinching, A.J. and Mason, D.Y. Immunological detection of T and B cell populations in routine blood smears. Lancet, 1984; 1: 1042.
2. James, D.G. and Studdy, P.R. A colour atlas of respiratory disease. London, Wolfe Medical Publications, 1981.
3. Friedman-Kien, A.E., Laubenstain, L.J., Rubinstein, P., Buimovicir- Klein, E., Marmor, M., Stahl, R., Spigland, 1., Kim, K.S. and ZollaPazner, S. Disseminated Kaposi’s sarcoma in homosexual men. Ann. Intern. Med., 1982; 96 :693.
4. Eyster, M.E., Goedert, J.J., Poon, M.C. and Preble, O.T. Acid.Iabile alpha interferon. A possible preclinical marker for the acquired immunodeficiency syndrome in haemophilia. N. Engi. J. Med., 1983; 309:583.
5. Buimovici-Klein, E., Lange, M., Klein, R.J., Cooper, L.Z. and Grieco, M.H. Is presence of interferon predictive for AIDS? Lancer, i983; 2:344.
6. Kaposi, M. Idiopathisches multiples pigmentsarkom der Haut. Arch. Dermatol. Syph., 1872; 4: 265.
7. Modlin, R.L., Mayer, P.R., Ammann, A.J. Rca, T.H., Hofman, F.M., Vaccaro. S.A., Conant, M.A., and Taylor, C.R. Altered distribution of B and T lymphocytes in the lymph nodes form homosexual men with Kaposi’s sarcoma. Lancet, 1983; 2:768.
8. Barre - Sinoussi, F., Chermann, J.C., Rey, F., Nugeyre, M.T., Chamaiet, S., Gruest, J., Dauguet, C., Axler-Blin, C., Vezinet-Brun, F., Rouzioux, C., Rozenbaum, W. and Montagnier, L. Isolation of a T-lymphotropic retrovir.us from a patient at risk for acquired immune deficiency syndrome (AIDS). Science,
9. Vilmer, E., Barre-Simoussi, F., Rouzioux, C. et al. Isolation of new lymphotropic retrovirus from two siblings with haemophilia B, one with AIDS. Lancet, 1: 1984. 220:868.
10. Gallo, R.C., Salahuddin, S.Z., Popovic, M. et al. Frequent detection and isolation of cytopathic retroviruses (HTKV-IH) from patients with AIDS and at risk for AIDS. Science, 1984; 224 : 500.
11. Popovic, M., Sarngadharan, M.G., Read, E. and Gallo, R.C. Detection, isolation and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science, 1984; 224:497.
12. Schupback, J., Popovic, M., Gilden, R.V. and Gond, M.A., Senngadharan, M.G., Gallo R.C. Serological analysis of a subgroup of human T-lymphotropic retroviruses (HTLV-III) asso­ciated with aids. Science, 1984; 224 : 503.
13. Brun-Vezinet, F., Rouzioux, C., Barre-Sinoussi, F. and Saimot, A. C. Detection of lgG antibodies to lymphadenopathy associated virus (LAy), in patients with acquired Immunodeficiency syndrome or lymphadenopathy syndrome. Lancet, 1984; 1: 1253.
14. Cheingsong-Popov, R., Weiss, R.A., Daigleish, A. et al. Prevalence of antibody to human T-Lympo­ tropic virus type III in AIDS and AIDS-risk patients in Britain. Lancet, 1984;2 : 477.
15. Melbye, M., Biggar, R.J., Ebbesen, P., Sarngadharan, M.G.,Weiss, S.H., Gallo, R.C. and Blattner, W.A. Seroepidemiology of HTLV-III antibody in Danish homosexual men; prevalence, trans­ mission, and disease outcome. Br. Med. J., 1984; 289: 573.
16. Luft, B.J., Conley, F., Remington, J.S., Layerdiere, M., Wagner, K.F., Levine, J.F., Craven, P.C., Straudberg, D.A., Fib, T.M., Rice, N. and Meunier-Carpentier, F. Outbreak of central-nervous-system toxoplasmosis in Western Europe and North America. Lancet, 1983; 1:781.
17. Gruer, L. D., McKendrick, M.W. and Geddes, A.M. Pneumococcal bacteraemia; a continuing challenge. Q. J. Med., New Series LIII., 1984; 210: 259.
18. Roy, D. The spleen preserved. Br. Med. J., 1984; 289; 70.

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