Immunoglobulins and hypersensitivity in human immunodeficiency virus (HIV) infection

THE JOURNAL OF

ALLERGY AND

CLINICAL

IMMUNOLOGY NUMBER 1

VOLUME 84

Editorials lmmunoglobulins and hypersensitivity in human immunodeficiency virus (HIV) infection

The epidemic acquired immune deficiency syndrome is now known to be due to retroviral infection with HIV-1 and HIV-2. Current knowledge regarding these infectious agents has been summarized in thi4 JOLWAL. The risk for disease progression has been studied best in male homosexuals. In the San Francisco City Clinic Cohort Study, 6700 homosexual and bisexual men who enrolled in studies of hepatitis B between 1978 and 1980 have been followed for subsequent development of AIDS since late 1983. As of September 1987, 75% of all cohort members have HIV infection and 804 cases of AIDS have been reported.’ Thirty-six percent of the HIV-infected male homosexuals have progressed to AIDS after X8 months of infection, whereas 140% were symptomatic and only 20% were completely asymptomatic. In studies of other adult risk groups, such as hemophiliacs and posttransfusion recipients, the cumulative incidence of AIDS is similar to that noted in homosexual men. AIDS has been noted in about 30% of hemophiliacs older than 21 years within 6 years after infection, whereas a 35% risk of AIDS has been estimated in transfusion recipients within 5 years of infection. Although only time will clarify the ultimate frequency of progression to AIDS. it is reasonable to expect that cumulative frequency is likely to increase well above the 36%. Disease progression appears to be higher in the first year Iof life in perinatally infected infants. Hints of more rapid disease progression in intravenous abusers and ti:)mcn remain to be substantiated.

Ahlnm~itr~iot~s used AIDS: Acquired Immunodelicrcncy \yndrome HIV: Human immunodeficicncy viruz? WR-5: WR-6: Walter Reed Hospital staging classitication 5 and 6 of HIV infection IL-4: IL-S: Inter&kin 4 and 5 T,,: Helper T cell

Lui et al..’ based on a cohort of 83 homosexual and bisexual men, used a model to determine that the maximal likelihood estimate for the proportion of infected homosexual men developing AIDS was 0.99 (90% confidence interval ranging from 0.38 to 1). In addition. the maximum likelihood estimate for the mean incubation period for AIDS in homosexual men was 7.8 years (90% confidence interval ranging from 4.2 to 15.0 years), a result that is similar to the estimate of 8.2 years for adults developing transfusionassociated AIDS. There is obvious need to develop markers to monitor HIV-infected patients, both for progress and early intervention, as well as for stratification in treatment trials. Several markers that have been studied as prognostic elements are listed in Table I. ‘ ’ CD4 lymphocyte levels, P,-microglobulin, and HIV ~24 antigen levels have been repeatedly identified as useful markers. Fling et al.” report that serum IgA concentration. in patients

with

HIV

seropositivity.

may bc a useful 1

2 Grieco

TABLE 1. Some clinical, serum protein, and cellular markers of evolution toward AIDS in HIV-infected individuals

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Hairy Ieukoplakia Oral candidiasis Pz-Microglobulin increase Neopterin increase Acid-labile interferon increase IgG and IgA level increases High-titer cytomegalovirus antibody p24 Antigen increase Decreasedp17 and p24 antibodies CD4 lymphocyte-subsetdecrease<400 to <200/cm Selective decrease4B4 + lymphocytes

marker of immunologic progression of disease. In a study of 107 HIV antibody-positive patients, IgA levels >300 mg/dl were consistently noted in subjects in staging classification 5 (WR-5) of Walter Reed Hospital (<400 CD4-positive cells plus thrush or complete anergy) and WR-6 (opportunistic infection). For WR-6 stage, the assay was reported to be 100% sensitive and 73% specific, but the positive predictive value was only 32%. Since WR-6 stage involves a readily available diagnosis manifested by opportunistic infection, prognostic tests would be more valuable that occur during the development of lesser manifestations. Even if both WR-5 and WR-6 are included, the positive predictive value increases to 66%, which is still not adequate for assessmentof individual patients. Other investigators have also reported increased IgA levels with progressive disease.‘. ’ Although this assay appears limited when it is used alone for prognostication, it may ultimately prove useful as a component in a panel of markers. Augmentation of IgA levels most likely results from HIV-related polyclonal hyperreactivity of the B cell limb that accompanies the deficient antibody response to new antigen that is characteristic of the immunodeficiency in HIV infection.’ The cause of B cell hyperreactivity is unclear. Both Epstein-Barr virus and cytomegalovirus are polyclonal B cell activators and are believed to contribute to this phenomenon. In addition, it appears that HIV itself or subunits of the virus can polyclonally activate B cells in vitro. However, the mechanism of B cell activation in this disease remains to be elucidated. Recently, Coffman et al.‘O and Bond et al.” demonstrated that IL-5 acts on lipopolysaccharide-stimulated murine B cells to induce a threefold to sixfold increase in IgA secretion without increasing the synthesis of any of the IgG subclasses or IgM. If the activity of IL-5 is IgA isotype

J. ALLERGY

TABLE II. Some clinical manifestations infection suggestive of hypersensitivity mechanisms

CLIN. IMMUNOL. JULY 1989

of HIV

1. Increasedatopic manifestationswith responseto recombinant interferon-y ” 2. Eosinophilic pustular folliculitis ” 3. Eosinophilic vasculitis ” 4. Sulfonamide-trimethoprim sensitivity ” 5. Pyrimethamine-sulfadoxinesensitivity ” 6. Phenytoin sensitivity I0 7. Severeallergic contact dermatitis ” 8. Severechronic photosensitivity I” specific in part, it is tempting to speculate that a dysregulation involving IL-5 may be involved in the increased IgA levels noted with AIDS. The effect of IL-5 may involve an isotype-specific switching capacity or action on postswitch IgA B cells. It may be important to note that eosinophil production is stimulated by IL-5 as well. Mosmann and Coffman” have identified two classes of helper T cells in mice that secrete differing groups of lymphokines. The T,, cell secretes interferon-2 and interferon-y, whereas the T,, cell secretes IL-4 and IL-5, as well as granulocyte/ monocyte colony-stimulating factor. This suggests that the T,, cell, if the situation is similar in humans, might influence IgA B cell development in HIV infection. Another immunoglobulin class that has received some attention in HIV infection is IgE. Lowenstein et al.” reported progressive increases of IgE protein levels with HIV infection and noted that IgE increased simultaneously from 105 2 25 to 5 19 t 306 in 27 patients whose CD4 cells decreased markedly. Similar findings have been noted by Quirino et al. I4and Wright et al. I5 but not confirmed by Ring et al. I6 Serial antigen-specific IgE antibodies have not been studied adequately to determine changes in levels and any relationship to clinical allergic sensitivity. Carini et al.” have reported results indicating that HIVinfected T cells release an IgE-binding factor and that virus infection might also enhance the expression of Fc, receptor on these T cells. In addition, Pederson et a1.18reported HIV antigen increased histamine release with cells from 80% of patients with AIDS, suggesting the presence of HIV-specific IgE antibodies. Anti-IgE-mediated histamine release has been noted to be increased in HIV-infected subjects as we11.19 HIV infection has been dominated clinically by sequelae that primarily reflect immunodeficiency. How-

VOLUME E4 NUMBER

ever, it !s possible that immune dysregulation may con tribute to some disease manifestations by hypersensi-tivity mechanisms, including IgE. The reduction 01 elimination of tl-ie suppressor component of IgE and eosinophil regulatory mechanisms by cyclophosphamide in mice might represent an analogous situation that may occur in human HIV infection. Recent information regarding IgE synthesis indicates that IgE production by normal human B cells is mediated by IL--i and suppressed by interferon-y.“’ It is again tempting to speculate that reduced T,, interferon-y, with 01 without augmented THzIL-4, might act to lead to polyclonal actuation of IgE B cells. There appears to he ;I strong correlation between the induction of Fc, receptor I1 (C’D23) expression on B cells by IL-4 and 1gF production. HI\’ infection may represent an opportu nity to cxammc a mild induced disorder of IgE regu lation. Some manifestations of HIV infection that sug gest that humoral and cellular hypersensitivity me& anisms may contribute to drug reactions. as ucli zj other clinical sequelae, are listed in Table II. HI\ infection has induced catastrophic illness anti clearlq represents a global calamity. One stnall gain may be home ilnproved understanding of the role 01 T-lymphocyte subsets and their interleukinh in the regulation of both IgA and IgE B cell\. Michuel H. Grieco. Ml) it. Lu,k’.si Roosevelt Hospital Crntrr 428 w. 59th St. Nor1 York. NY IOOIY

REFERENCES I. Soto-Apuilar MC, deShazo RD. Human retrowruses and the acquired immunodeficiency syndrome. I. Vimlog> updare [CME article] J ALLERGY CLIH IMMUNOI. l%X;XI:hl9. 2, Curran JW, Jaffe HW, Hardy AM. Morgan WM, Selih Rbl. Dondero TJ l:pidemiology of HIV infection and AIDS In 111: United State\ Science 1988:239:610. 3. Lui K-J, Darlow WW, Rutherford GW III. A model-bawd cximate of the mean incubation period for AIDS in homo\euu;tl men. Science 1988:240:1333. 4. Polk BF, Fox R, Brookmeyer R, Kanchanaraksa S. Ktislw RI Visscher H, Rinaldo C, Phair I. Predictor5 of AIDS dcvcloping in 3 cohort of acropositive homosexual men. N Engl J Mcd 1987:316:62. 5. Moss AR, OLmond D. Bacchetti P, Chaisson R, Krampt W ROQ E. Predxting progression to AIDS: implications of (11~ San Francisco General Hospital Cohort Study tar early Intervention [Abstract No. 41371. Proceedings of Ihe Fourth Inter national AIDS Conference. Stockholm, Sweden. June I ?- I h 1988. p 294. 6. Fling JA. Fixher JR Jr, Bowel1 RN. Reid MJ. The relahon,hip of serum IgA concentration to human immunodellctzncy virus (HIV) infection: a crowsectwnal stud!, 01 HIV-wwpw!tivc individuals detected by wrccning m ihc

J. ALLERGY

24. Greenberger PA, Patterson R. Management of drug allergy in patient with AIDS. J ALLERGY CLIN IMMUNOL 1987;79:484. 25. Gottlieb MS, Young LS. Adverse reactions to pyrimethaminesulfadoxine in context of AIDS [Letter]. Lancet 1985;l: 1389. 26. Hostettler C, Amundson D, O’Connor S. Phenytoin hypersensitivity with pulmonary involvement in a hemophiliac patient with human immunodeticiency virus infection. Drug Intel1 Clin Pharm 1987~2I :875.

27. Rietmeijer CA, Cohn DL. Severe allergic contact dermatitis from dinitrochlorobenzene in a patient with HIV infection [Letter]. Arch Dermatol 1988;124:490. 28. Toback AC, Langley J, Cardullo AC, Doddy U, Romagnoli M, DeLeo VA. Severe chronic photosensitivity in association with AIDS [Letter]. J Am Acad Dermatol 1986:15:1056.

Quality assurance and standardization allergy extracts in allergy practice

“I think all of us will agree that standardization of extracts in their present forms is highly desirable.” ---Louis Tuft, MD. (From the minutes of the first business meeting of the American Academy of Allergy, December 12, 1944.)

At its very first meeting, the American Academy of Allergy adopted a policy requiring that all authors of articles about allergy extracts presented at the meetings or published in THE JOURNAL OF ALLERGY use a standard unit, the PNU. Their purpose was not only to speak a common language to be able to compare results of one research study with another but also to provide consistent reliable materials for diagnostic testing and immunotherapy. In adopting this policy, the Members clearly intended that standardized extracts be used in daily practice, although the Members could legislate only the official policy of the Academy. During the discussion of this policy on the floor of the meeting, the thorny problems surrounding standardization and quality assurance of extracts used for diagnosis and treatment of allergic diseases were addressed. Our predecessors intuitively recognized what we now know experimentally, that these extracts are not only exceedingly complex and variable but also that different individual patient’s antibodies may recognize different components in the same extracts. The Members of the Academy in 1944 were quite aware that their agreement on PNU was merely a temporary solution that would need refinement as new knowledge and techniques developed, but they believed that an imperfect

unit was better than no unit at all. The

Members also recognized the three general approaches available for comparing extracts: 1. Measurement of concentration of allergenic molecules (in 1944 by protein nitrogen content, in 1989 4

CLIN. IMMUNOL. JULY 1989

of

Abbreviations used PNU: Protein nitrogen unit AU: Allergy unit WHO: World Health Organization BU: Biological units FDA: Food and Drug Administration IEF: Isoelectric focusing CRIE: Crossed radioimmunophoresis PAGE: Polyacrylamide gel electrophoresis

by immunochemical techniques with polyclonal or murine monoclonal antibodies to the major individual allergens when this was available, or pooled human IgE antibodies to measure total allergenic activity by RAST inhibition, supplemented by CRIE or immunoblotting) 2. Measurement of biologic activity (in 1944 by skin testing, in 1989 still mainly by skin testing supplemented by basophil histamine release or inhalation challenge tests) 3. Consideration of the quality of the source materials and their handling (in 1944 as well as 1989 by taxonomy and careful attention to details of collection or culture, storage of the source materials, and manufacture of the extracts) Of course, since 1944, there have been important advances in protein chemistry, bioassay techniques, and allergen preparation. Advances in assay techniques have been in both in vitro as well as in vivo test methods. Examples of in vitro test methods include assays for specific allergens, such as hyaluronidase in insect venoms and Amb a I (antigen E) in ragweed pollen. In addition, there are a variety of