INTERNATIONAL JOURNAL OF LEPROSY^ Volume 57, Number 4

Printed in the U.S.A.

CORRESPONDENCE

Tiiis department is .10r the publication of informal communications that are ql.interest becausv they are informative and stimulating, and .10r the discussion ofcontroversial incuto-s. The mandai(' of this formv.,u, is to disseminate informationrelating to leprosy in particular and also other mycobacterial diseases. DissidentC0111111e111 01' illtelpalali011 011 published roscarei! is o!' course valid, but personalityattacks on individuais would secin unnecessary. comments, valid or 1101,

also are unwelcome. They might result in intederence with the distribution of the.louRNAL and tinis imo:fere with its prime purpase.

Fiftieth Anniversary of the"N-Factor/Hansen-anergic Fringe"

Hypothesis for Hanseniasis

TO THE EDITOR:

The "N-Factor/Hansen-imergic fringe"(NF/HAF) hypothesis for hanseniasis waspostulated in Brazil in 1937 (9, and inter-nationally reported ai the Cairo Congress in1938 (3) and the Sixth Pacific Science Con-gress (San Francisco) in 1939 (12. 13). Differ-ing from the then prevailing notions thatpredisposition to hanseniasis dependedprincipally on age and/or debilitation dueto malnutrition and various diseases, thehypothesis maintained that it was probablyrelated to genetic factors. Stimulated byHansen's bacillus, the majority of the pop-ulation (75%-80%) would react in variousdegrees to the Mitsuda test due to the pres-ence of a "natural" (N) factor of resistancethat would protect them against the devei-opment of the disease or, at most, permitthe organization of nonbacillary sarcoid ortuberculoid-like lesions in the skin and/ornerves. The minority, the "anergic fringe"—a term tater changed to "Hansen-anergicfringe" in order to stress its specificity —would not react and, with the cooperationof "accessory factors" (malnutrition, dis-cases, etc.), would eventually develop ba-cillary, Virchow's cell-loaded lesions. "In-termediate" aspects could appear betweenthose extremes of reactivity. The differentdegrees of reactivity might help in estab-lishing a new classification of forms of thedisease.

The NF/HAF hypothesis was sympa-

thetically accepted in editoriais of theINTERNATIONAL JOURNAL OF LEPROSY (5) andother periodicals (''. '8), and was entirely orpartially accepted in many articles and text-books. It is practically incorporated in mod-em hansenology, in spite of the fact that itsgenetic foundation is not ■,'et fully con-firmed. After a study of the influence of.Ify-coliacterium tuberculosis and BCG on theMitsuda reactivity, the hypothesis was com-pleted in 1957 ('4) to admit their stimulatingcapacity for Mitsuda-positi \ration in the NFmajority. However, since the HAF was notreduced, the failure of BCG as a preventivevaccine was forecast 12 years before thepractically negative value of the vaccinationexperiments in Burma were reported by theWorld Health Organization (WHO). Thesame forecast has been made (16) for othervaccines as well if they do not change thereactivity of the HAF.

Curiously. the origin, authorship and ter-minology of the 50-year-old hypothesisgradually faded away and many other au-thors — with as many new terms— have beencredited with its postulation. At least 24pairs of synonyms have replaced the termNF/HAF, of which the more commonlyused are "innate cell-mediated immunity/defect of cell-mediated immunity," "natu-ral reactivity/natural nonreactivity," "con-stitutional immunity/constitutional aner-gy," and others (IS).

Professor Newell (7) is the author most

864

57, 4^ Correspondence^ 865

often credited with the etiopathogeneticaland epidemiological viewpoints of the NF/HAF hypothesis after he wrote that ".From the epidemiological standpoint the`anergic' or factor N hypothesis describingthe lepromin reactions and lepromatousleprosy appears to be the most acceptable...." adding new facts favoring the hypoth-esis, which "seems to be the one most con-sistent with known occurrences." However,certainly unaware of the original articles of1937-1939 (1"' 12. 13), he also wrote that "oneof the leading advocates of this hypothesisis Rotberg. 1957)" emphasis added). Theseunderlined inexactitudes were aggravatedby a favorable appreciation of Prof. New-ell's article by WHO (10) in which the orig-inal papers and dates of publication wereomitted, easily leading the reader to attrib-ute the NF/HAF hypothesis to Prof. Newell.

One of the results is that in the INTERNA-TIONAL JOURNAL OF LEPROSY ÍrOnt 1975 to1988, 12 articles cite Prof. Newell as theauthor of the etiopathogenetical and epi-demiological viewpoints of the NF/HAFhypothesis. For instance, Nakajima, et al.(6) write that a "special depression of cell-mediated immunity in the lepromatous formis a host-dependent characteristic whichprobably is genetically determined." Har-boe editorializes that "Epidemiologicalstudies indicate that susceptibility to lep-romatous leprosy is, at least partly, geneti-cally determined." and Chirmule, et al.refer to the ". . . lepromin-negative healthysubjects who represent a high-risk group inleprosy-endemic arcas." Ali these state-ments are attributed to Prof. Newell, in spiteof having been clearly postulated 50 yearsago at the Cairo and San Francisco Con-gresses ( 10 . 12 ' 13 ).

With whichever authorship of terminol-ogy, what is important is that, at its 50thanniversary, the NF/HAF hypothesis ap-pears to be well implanted, although moreconfirmatory genetical evidence is neces-sary. However, in spite of the fact that re-cent works such as those of Languillon (4),Price, et al. (8), and Rea and Levan (9), andStoner ('') have given credit to the originalauthor, it seems that the Brazilian contri-bution to this advance could soon be for-gotten.

-Abrahão Rotberg

Professor of Dertnatology (1958-1973)Escola Paulista de MedicinaSão PauloAssociate Prol: of DermatologyFaculo, ofiNledicineSão Paulo, BrazilRua Pedroso Alvarenga 125/74São Paulo 04531, Braril

REFERENCES1. CHIRMULE, N. B. Immunogenic "subunit" of the

ICRC antileprosy vaccine. Int. J. Lepr. 56 (1988)27-35.

2. HARBOE, M. Immunological aspects of leprosy:ten years' activity at the Armauer Hansen Re-search Institute and prospects for further work.(Editorial) Int. J. Lepr. 48 (1980) 193-205.

3. Immunology and serology. In: Editorial on theCairo Congress number. Int. J. Lepr. 6 (1938) 3-74.

4. LANGUILLON, J. Precis de léprologie. Les facteursimmunologiques. Acta Leprol. (Geneve) 6 (1988)322.

5. MUIR, E. The unknown factor in leprosy. (Edi-torial) Int. J. Lepr. 7 (1939) 269-272.

6. NAKAJIMA, S., KOBAYASHI, S., NOHARA, M. andSATO, S. HLA antigen and susceptibility to lep-rosy. Int. J. Lepr. 45 (1977) 273-277.

7. NEwELL, K. W. An epidemiologist's view on lep-rosy. Bull. WHO 34 (1966) 827-857.

8. PRICE, M. A., ANDERS, E. M., ANDERS, R. F.,RUSSELL, D. A. and DENNIS, E. S. Cell-mediatedimmunologic status of healthy members of fam-ilies with a history ofleprosy. Int. J. Lepr. 43 (1975)307-313.

9. REA, T. H. and LEVAN, N. E. Current concepts inthe immunology of leprosy. Arch. Dermatol. 113(1977) 345-352.

10. ROTBERG, A. Some aspects of immunity in lep-rosy and their importance in epidemiology, path-ogenesis and classilication of forms of the disease.Rev. Bras. Leprol. 5 (1937) 45-97.

II. ROTBERG, A. Immunity in leprosy. Reviewed inLepr. Rev. 10 (1939) 130-132.

12. ROTBERG, A. Influence of allergy in pathogenesisofleprosy. In: Proceedings of the Sath l'acific Sci-ence Congress, San Francisco, California, 1939,pp. 977-982. Abstract in Int. J. Lepr. 8 (1940)558-559.

13. ROTBERG, A. Modern trends in the study of theepidemiology ofleprosy; importance of hereditaryfactors. In: Proceedings of the Sixth Pacific ScienceCongress, San Francisco, California, 1939, pp. 939-945. Abstract in Int. J. Lepr. 8 (1940) 556.

14. ROTBERG, A. Fator "N" de resistência à lepra erelações com a reatividade leprominica e tuber-culinica. Valor duvidoso do BCG da imunizaçãoantileprosa. Rev. Bras. Lepro. 25 (1957) 85-106.

866^ International Journal of Leprosy^ 1989

15. ROTBERG, A. The specific defect of immunity tohanseniasis ("anergic margin")—a 40-year-oldBrazilian theory. (Editorial) Hansenol. Int. 2(1977)12-14.

16. ROTBERG, A. The "Hansen-anergic Fringe" andrenewed doubts about vaccination. (Letter) Int. J.Lepr. 51 (1983) 12-14.

17. STONER, G. I. Ir genes and leprosy. Int. J. Lepr.46 (1978) 217-220.

18. The lepromin test. (Editorial) Lepr. India 12(1940)115-116.

19. World Hcalth Organization. Conclusions of K.W. Newell's "An epidemiologist's view on lep-

rosy." WHO Chronicle 20 (1966) 460-461.

Failure to Detect Antibodies to HIV-1 in Sera fromPatients with Mycobacterial Infections

To THE EDITOR:The infection of humans with the human

immunodeficiency virus type 1 (HIV-1) ini-tiates a slow progressive degeneration of theimmune and central nervous system (1'3).

The resulting complex disorder clinicallyrecognized as the acquired immunodefi-ciency syndrome (AIDS) is often compli-cated by mycobacterial infections (2). Re-cently, SrivRaj, et al. (6) published in theJOURNAL an article indicating that whentested by immunoblotting, sera from 76.6%of leprosy patients (33 out of 43), 33.3% oftuberculosis patients (7 out of 21), and 80%of leprosy contacts (4 out of 5) contam n IgGclass antibodies against HIV-1. The IgG an-tibodies specific for HIV-1 p24, the majorantigen of this virus, werc present in 17 ofthese 69 persons. None of 63 healthy con-trols had anti-HIV p24, and only one con-trol tested positive for anti-HIV p17. Onthe basis of these results, the authors claimthat HIV-1 and mycobactcria share com-mon antigenic determinants. This couldhave important implications for the devei-opmcnt of HIV vaccines, which (if the an-tibodies were neutralizing) could consist ofrelevant neutralizing HIV antibody-induc-ing antigenic determinants of mycobacteria.

In order to study this possibility, we de-cided to examine the HIV-binding and HIV-neutralizing capacity of leprosy sera. Thesera wcre obtained from 16 patients withlepromatous leprosy, 6 paticnts with tuber-culoid leprosy, and 10 control healthy vol-unteers in two different arcas, Agra in Indiaand Surabaya in Indonesia. For the dctec-tion of anti-HIV-1 antibodies, we used a

sensitive and specific immunoblotting pro-cedure described in detail elsewhere (7). Inbrief, after the separation on SDS-polyac-rylamide gels, protein preparation from H9cells infected with the HTLV-11111isolate ofHIV-1 (S) and from control uninfected H9cens were blotted onto nitroccllulose, andthe nitrocellulose strips with blotted pro-teins were exposed to the sera, includingpositive and negative controls. The reactionof the sua with HIV-proteins was visual-ized using '251-labeled mouse monoclonalanti-human IgG and autoradiography (TheFigure). None of the 22 scra from patientswith leprosy contained IgG antibodics spe-cific for HIV-1 proteins, although weakbinding for non-HIV, probably cell-de-

18

kDa

55- —

24- filb

THE FIGURE. HIV-1-specific immunoblots of a rep-

resentative experiment demonstrating the detection of

antibodies to HIV-1 antigens. A serum sample from a

seropositive hemophiliac (track I) contains HIV- I -specific antibodies (positive control); leprosy scra (tracts

2-18) cicarly do not show any reactivity with HIV-Iantigens.