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Disease Versus Disease: How One Disease May Ameliorate Another

Department of Pediatrics, Mattel Children's Hospital at UCLA, Los Angeles, California

	ABSTRACT

TOP ABSTRACT EDWARD JENNER AND VACCINATION THE HETEROZYGOTE ADVANTAGE RECEPTOR-DEFICIENCY PROTECTION DRUG DISCOVERY FOR YOUNG... NATURAL IMMUNOSUPPRESSION UNDERNUTRITION MAY BE GOOD... THE MYSTERIES OF HIV... SUMMARY REFERENCES

 
Systemic disease, either genetic or acquired, may prevent or decrease the severity of another disease. These observations have led to important therapeutic advances. The best-known examples are Edward Jenner's use in 1798 of cowpox to prevent smallpox and J.B. Haldane's 1942 observation that erythrocyte disorders such as thalassemia and sickle cell disease modify the severity of malaria. Patients with and carriers of cystic fibrosis may have genetic resistance to tuberculosis and/or secretory diarrhea. The beneficial effects of undernutrition have led to therapeutic diets for seizures, celiac disease, type 2 diabetes, and inflammatory bowel disease. Finasteride for prostatic hypertrophy was developed after the observation that patients with male pseudohermaphrodism resulting from 5--reductase mutations do not develop prostatic hypertrophy. Rh immunoglobulin for Rh hemolytic disease prevention followed the observation that ABO incompatibility prevented Rh sensitization. The natural immunosuppression of measles may cause remission of nephrosis, and that of leprosy prevents psoriasis. Patients with one form of agammaglobulinemia (X-linked) never get Epstein-Barr virus infection, and patients with another form (common variable) are seemingly cured by HIV infection. HIV/AIDS is prevented or modified by co-receptor mutations (notably the CCR32 chemokine mutation), HIV-2, or GB virus C infection. Additional exploration of these genetic, infectious, and metabolic influences on disease severity may provide new therapeutic approaches to HIV and other diseases.

Key Words: HIV • vaccination • receptor deficiency • agammaglobulinemia • starvation

Abbreviations: CF—cystic fibrosis • CFTR—cystic fibrosis transmembrane conductance regulator • EBV—Epstein-Barr virus • XLA—X-linked agammaglobulinemia • CVID—common variable immunodeficiency • GBV-C—GB virus type C

It is common knowledge that many illnesses predispose to another, eg, influenza to pneumonia, diabetes to arteriosclerosis, and obesity to hypertension, to name just a few. The converse concept, disease versus disease (how certain illnesses prevent or ameliorate another) is less well known, is more intriguing, and has led to important therapeutic advances.

Systemic disease has widespread effects on many organs and systems, usually greater than even a powerful systemic drug. In genetic disease, these effects are lifelong and for the carrier may lead to a survival advantage, the so-called heterozygote advantage. Here I illustrate a dozen of these disease pairs, review their therapeutic implications, and suggest additional applications, particularly in regard to HIV/AIDS.

	EDWARD JENNER AND VACCINATION

TOP ABSTRACT EDWARD JENNER AND VACCINATION THE HETEROZYGOTE ADVANTAGE RECEPTOR-DEFICIENCY PROTECTION DRUG DISCOVERY FOR YOUNG... NATURAL IMMUNOSUPPRESSION UNDERNUTRITION MAY BE GOOD... THE MYSTERIES OF HIV... SUMMARY REFERENCES

 
Immunization, perhaps the most important therapeutic advance in medicine, resulted from a disease-versus-disease observation. Knowing that milkmaids with cowpox were seemingly resistant to smallpox, in 1778 Dr Edward Jenner of Glouchestershire, United Kingdom, inoculated material from a cowpox sore of milkmaid Sarah Nelmes into the arms of several teenage boys. One boy, James Phipps, was subsequently exposed to smallpox and found to be fully protected.¹

Smallpox vaccination, using cowpox (vaccinia) virus, induces an antibody response that renders the recipient immune, presumably by stimulating long-lasting cross-reactive antibodies.²

This experience illustrates the first use of vaccine, introduced the concept of an attenuated pathogen, and serves as an introduction to the disease-versus-disease concept.

	THE HETEROZYGOTE ADVANTAGE

TOP ABSTRACT EDWARD JENNER AND VACCINATION THE HETEROZYGOTE ADVANTAGE RECEPTOR-DEFICIENCY PROTECTION DRUG DISCOVERY FOR YOUNG... NATURAL IMMUNOSUPPRESSION UNDERNUTRITION MAY BE GOOD... THE MYSTERIES OF HIV... SUMMARY REFERENCES

 
Malaria and Erythrocyte Disorders
The best-known example of a genetic trait influencing the response to an infectious disease is the modification of malaria by red cell disorders. In 1948 J.B. Haldane proposed that malaria was an evolutionary force by selecting for malaria-resistance genes, thus enhancing survival of patients with thalassemia major and minor (the carriers) by providing the so-called heterozygote advantage.^3,4 Malaria, particularly Plasmodium falciparum malaria, is a leading cause of death in the world and is particularly deadly in young children.

Other erythrocyte abnormalities, notably sickle cell disease but also hemoglobin C or F disease, glucose-6-phosphate dehydrogenase deficiency, ovalocytosis, and elliptocytosis, provide a survival advantage even among heterozygotes.^5,6

Many studies have validated Haldane's conjecture by showing a higher frequency of these disorders in tropical regions with high malaria incidence as compared with adjacent mosquito-free highlands, reduced morbidity and mortality (up to 50%), and decreased numbers of circulating parasites (by 80%)⁷ The mechanism of resistance may consist of decreased parasite replication within the erythrocyte or enhanced splenic clearance of parasitized erythrocytes.⁵

Cystic Fibrosis, Tuberculosis, and Secretory Diarrhea
Cystic fibrosis (CF), the most common genetic disease of Northern European populations, occurs in 1 in 4000 individuals and has a carrier rate of 1 in 25 to 1 in 50. Two plausible theories have been proposed for a CF heterozygote advantage: resistance to tuberculosis and resistance to infectious diarrheas.

Tuberculosis was the greatest single cause of death in the Western world well into the 20th century.⁸ Its chronicity and usual limitation to the lung suggests considerable host resistance that may be under genetic control. The CF gene has accumulated in European populations to a much higher degree than in American Indian, Asian, and black African populations, and these ethnic groups have a higher degree of susceptibility to tuberculosis.

Pulmonary tuberculosis is exceedingly rare among patients with CF despite the fact that these patients are malnourished, have preexisting lung disease, and often have received steroid treatment. Crawford⁹ first pointed out a paucity of tuberculosis among his CF patients. Wood et al,¹⁰ in a review of 700 patients with CF who were managed over 18 years, found only 2 cases of tuberculosis. Others^11–14 have reported atypical tuberculosis in patients with CF, but these cases are usually extrapulmonary.

Meindl⁸ postulated that the increased production of mucopolysaccharides in patients with CF help to surround a tuberculous pulmonary focus, inhibiting fluid exudation and preventing spread to adjacent lung parenchyma.

Quinton¹⁵ postulated that patients with and carriers of CF may be less susceptible to severe secretory diarrhea (caused by Vibrio cholarae, Escherichia coli, rotavirus, etc), which results from a defect in the CF transmembrane conductance regulator (CFTR), the genetic abnormality that is present in CF. A CFTR mutation inhibits chloride transport in fluid-transporting tissues such as intestinal cells and sweat glands, which results in chloride being preserved and intestinal fluid loss being minimized during secretory diarrhea.

Indeed, pharmacologic inhibitors of CFTR under development reduce enterotoxin-induced intestinal fluid secretion in mouse, rat, and human intestinal-loop models of toxin-induced secretory diarrhea.^16,17

Bubonic Plague and the CCR32 Mutation
A 32-base-pair mutation of the gene for a chemokine receptor on hematopoietic cells (the CCR32 mutation) provides resistance to HIV, because CCR is the co-receptor for monocytotrophic strains of HIV, and without a normal co-receptor, viral attachment cannot occur (see "The Mysteries of HIV Infection"). Stephens et al¹⁸ have shown that this mutation appeared 700 years ago in populations living in areas affected by the devastating bubonic plague epidemic of the 14th century, thus providing an explanation for its occurrence and persistence and making an important contribution to HIV pathogenesis and eventual treatment.

	RECEPTOR-DEFICIENCY PROTECTION

TOP ABSTRACT EDWARD JENNER AND VACCINATION THE HETEROZYGOTE ADVANTAGE RECEPTOR-DEFICIENCY PROTECTION DRUG DISCOVERY FOR YOUNG... NATURAL IMMUNOSUPPRESSION UNDERNUTRITION MAY BE GOOD... THE MYSTERIES OF HIV... SUMMARY REFERENCES

 
X-linked Agammaglobulinemia and Epstein-Barr Virus
The good news for patients with X-linked agammaglobulinemia (XLA), unlike up to 10% of patients with other primary immunodeficiencies, is the fact that they will not develop Epstein-Barr virus (EBV)-driven lymphomas. Indeed, they will never even develop EBV infection, because they lack B cells and thus lack CD21, the EBV receptor.¹⁹

Faulkner et al¹⁹ could not identify EBV in repeated throat washings of 6 patients with XLA (unlike in normal subjects in whom 14 of 20 were positive). Patients with XLA have no circulating EBV genome, cannot have EBV-transformed B-lymphocyte cell lines developed, have no EBV-specific cytotoxic T lymphocytes, and have no mucosal antibody to EBV.¹⁹ By contrast, patients with XLA are susceptible to other herpes viruses such as HHV-6, varicella-zoster, herpes simplex, and cytomegalovirus.

Other immunodeficiencies with absent B cells may similarly be resistant to EBV infection. In EBV-induced lymphoproliferation after transplantation, eradication of B cells with immunosuppression²⁰ or the anti-B-cell monoclonal antibody rituximab may control the disease.^21,22

Parvovirus B19 and Plasmodium vivax Malaria
Receptor deficiency (but without clinical illness) provides complete protection to 2 other common infections: Parvovirus and P vivax malaria.

Parvovirus B19 causes a common pediatric exanthem, slapped-cheek syndrome (erythema infectiosum) and, less commonly, arthritis, fetal hydrops, or aregenerative anemia.²³ The Parvovirus B19 receptor is the red cell P antigen_, a glycolipid of the erythrocyte membrane. Individuals who lack the P antigen (the pp phenotype), a very rare blood group (1 in 200000), are naturally resistant to B19 infection. Brown et al²⁴ showed that all 17 patients who they studied with the pp phenotype (including 6 from the Amish population in Ohio) had no Parvovirus antibodies, unlike the expected seropositivity of 70% among P-positive subjects. In vitro culture of pp bone marrow with Parvovirus did not result in viral proliferation or growth inhibition.

It has been appreciated since the 1930s that most black West Africans and black Americans are resistant to P vivax malaria but not to malaria from other species of malaria.²⁵ This occurs because the Duffy blood group determinants Fy^a and Fy^b are the receptors for P vivax, and most of these individuals (70–90%) are Duffy negative (eg, FyFy).^26–29 This phenotype is very rare in other racial groups.^28,29 Duffy-negative subjects are susceptible to P falciparum malaria. Similar to hemoglobinopathies, these genetic polymorphisms may provide a selective survival advantage in malarial areas.^28,29

The 3 conditions described above are the extreme examples of the many genetic variants that modify disease severity.

	DRUG DISCOVERY FOR YOUNG WOMEN AND OLD MEN

TOP ABSTRACT EDWARD JENNER AND VACCINATION THE HETEROZYGOTE ADVANTAGE RECEPTOR-DEFICIENCY PROTECTION DRUG DISCOVERY FOR YOUNG... NATURAL IMMUNOSUPPRESSION UNDERNUTRITION MAY BE GOOD... THE MYSTERIES OF HIV... SUMMARY REFERENCES

 
Clinical observations on 2 disease-versus-disease paradigms have provided the theoretical basis for the development of 2 widely used therapeutic agents, Rh immunoglobulin for hemolytic disease of the newborn and finasteride for prostatic hypertrophy.

Rh Immunoglobulin
Hemolytic disease of the newborn (hydrops fetalis) was first described in 1932,³⁰ but its cause had to await the discovery of the Rh factor in 1940.³¹ One year later, Levine et al³² found that 90% of the mothers of hydropic infants were Rh-negative, whereas their fathers and the affected infants were Rh-positive.

Rh typing of blood donors and recipients began in 1947, which prevented transfusion-induced isoimmunization of Rh-negative subjects but did not prevent pregnancy-induced isoimmunization³⁰

Levine et al^33,34 made the key observation that ABO incompatibility between mother and infant lessened the chance of maternal Rh sensitization. Indeed, Finn et al³⁵ identified abundant fetal red cells in the maternal circulation after ABO-compatible but not ABO-incompatible pregnancies and suggested that in the latter situations, the maternal anti-A or anti-B isoagglutinins rapidly removed the fetal erythrocytes and prevented sensitization. They also showed that Rh-positive cells were removed rapidly from the circulation of Rh-negative subjects who were given 10 mL of high-titered Anti-Rh (D) sera.

Working independently, Freda et al^36,37 showed that an anti-Rh human immunoglobulin could prevent sensitization among Rh-negative Sing-Sing prisoners immunized with Rh-positive erythrocytes. Clinical trials of Rh immunoglobulin in Rh-negative women commenced in 1960, leading to its licensure in 1968.³⁰ An intravenous form of Rh immunoglobulin is also of value in the treatment of immune thrombocytopenic purpura.³⁸

Rh immunoglobulin, now given routinely to Rh-negative women after delivery or abortion, has virtually eliminated the risk of Rh hemolytic disease of the newborn.

Finasteride
In 1974 a rare form of male pseudohermaphrodism was described in families from Dallas, Texas,³⁹ and the Dominican Republic⁴⁰ that was associated with a deficiency of the enzyme 5--reductase, which catalyzes the conversion of testosterone to dihydrotestosterone. These genetic males have ambiguous genitalia, and some are raised as females. At puberty they undergo incomplete virilization and never develop prostatic hypertrophy or male-pattern baldness.⁴¹

Based on these observations, scientists at Merck⁴² developed finasteride, a synthetic oral 5--reductase competitive inhibitor. Finasteride was licensed in 1992 for the treatment of benign prostatic hypertrophy; it reduces prostate size with minimal adverse effects.⁴³ Finasteride may also lessen the incidence of prostatic cancer.⁴⁴

Finasteride is also approved for early male-pattern hair loss.⁴⁵ It also is used to reduce excessive hair growth in women with hirsutism such as that associated with polycystic ovary syndrome.⁴⁶

	NATURAL IMMUNOSUPPRESSION

TOP ABSTRACT EDWARD JENNER AND VACCINATION THE HETEROZYGOTE ADVANTAGE RECEPTOR-DEFICIENCY PROTECTION DRUG DISCOVERY FOR YOUNG... NATURAL IMMUNOSUPPRESSION UNDERNUTRITION MAY BE GOOD... THE MYSTERIES OF HIV... SUMMARY REFERENCES

 
Measles and Nephrosis
In 1947, Blumberg and Cassidy⁴⁷ reported partial or complete remission of 5 cases of nephrotic syndrome immediately after measles infection and identified similar cases in the earlier literature. In 1948, Janeway et al⁴⁸ gave measles to 12 children with refractory nephrotic syndrome: 8 experienced a complete remission, 1 experienced a partial remission, and 3 were nonresponsive. The remissions lasted 1 to 6 months and in 3 children persisted for at least 3 years.

Serial immune studies conducted by Lin and Hsu⁴⁹ in 2 children with nephrotic syndrome and intercurrent measles infection disclosed moderate immunosuppression with decreased T-cell subsets and lymphoproliferative responses. Cortisol levels were normal in 1 patient. The authors concluded that the likely mechanism for the remission was a temporary state of immunosuppression.

It is well recognized that tuberculin reactivity is diminished during measles infection.⁵⁰ Measles may reactivate tuberculosis.⁵¹ Manfredi et al⁵² recently reported the death of a previously healthy 17-year-old who succumbed to giant-cell pneumonia after concomitant measles and EBV-induced infectious mononucleosis associated with a profound CD4 lymphopenia. Other herpes viruses, notably cytomegalovirus, are associated with transient immunosuppression.

Norman Fost, MD (verbal communication, 2004), observed that 1 child with an extensive cavernous hemangioma had a striking regression during the stress of measles infection, leading to his 1968 report of the successful use of prednisone in 5 of 6 children with hemangioma.⁵³

Leprosy and Psoriasis
Only rare cases of the simultaneous occurrence of these 2 cutaneous disorders have been reported.^54–56 For example, Kumar et al⁵⁶ could identify only 20 patients with psoriasis among 146000 patients with leprosy. The postulated mechanisms include diminished cutaneous neuropeptides, inhibition of neurogenic inflammation, diminished cutaneous immune responses, and shared genetic factors.⁵⁷

	UNDERNUTRITION MAY BE GOOD FOR YOU

TOP ABSTRACT EDWARD JENNER AND VACCINATION THE HETEROZYGOTE ADVANTAGE RECEPTOR-DEFICIENCY PROTECTION DRUG DISCOVERY FOR YOUNG... NATURAL IMMUNOSUPPRESSION UNDERNUTRITION MAY BE GOOD... THE MYSTERIES OF HIV... SUMMARY REFERENCES

 
Celiac Disease and the Gluten-Free Diet
During Europe's 1944/1945 "winter of starvation," delivery of bread to the Juliana Children's hospital in the Hague was curtailed. Pediatrician Willem-Karel Dicke noted that a few of his patients flourished on a very restricted diet that included tulip bulbs; these children had celiac disease.⁵⁸ This confirmed Dr Dicke's long-held suspicion that wheat was the offending agent.⁵⁹ Dicke's classic dietary studies after the war, using growth curves and stool fat excretion, firmly established that gluten was the offending agent in celiac disease and that a gluten-free diet was the treatment of choice.⁶⁰

Seizures and the Ketogenic Diet
Jesus was asked how he was able to free a possessed child of the demons (seizures). He replied "This kind does not leave but by prayer and fasting" (Matthew 17:14–21). This scene is depicted In Raphael's final painting, the magnificent Transfiguration. Starvation was used throughout the middle ages as a treatment for seizures.

The modern ketogenic diet had its origin in 1911 with the report from Guelpa and Marie,⁶¹ indicating that a 4-day fast provided some control of seizures, followed in 1924 by Wilder's⁶² observation that the benefit of starvation could be obtained if ketonemia was produced by a diet rich in fat and low in carbohydrates. One year later, Peterman et al⁶³ reported that 69% of 57 patients treated with a ketogenic diet were seizure-free, and 35% were markedly improved.

With the introduction of Dilantin in1938, enthusiasm for the ketogenic diet waned but returned in the 1950s for drug-resistant seizures. It is still used today with considerable success for many drug-resistant patients.⁶⁴

The exact mechanism of action remains unclear.⁶⁴ Restriction of calories is an important part of the treatment. Ketones may exert an anticonvulsant effect, but no single ketone has been identified. An elevated ß-hydroxybutyric acid level has been proposed as a possible mechanism.⁶⁴

More palatable modifications of the ketogenic diet have been used including a medium-chain triglyceride diet⁶⁵ and, more recently, the Atkins diet.⁶⁶

Other Benefits of Undernutrition
Severe caloric restriction in experimental animals and probably humans can prolong life span.⁶⁷ Willi et al⁶⁸ used it with benefit in children with type 2 diabetes. Low-protein diets are of proven benefit in chronic renal disease.⁶⁹ A calorie-restricted diet has been used successfully in the treatment of inflammatory bowel disease⁷⁰ and childhood obesity with diabetes.⁷¹

	THE MYSTERIES OF HIV INFECTION

TOP ABSTRACT EDWARD JENNER AND VACCINATION THE HETEROZYGOTE ADVANTAGE RECEPTOR-DEFICIENCY PROTECTION DRUG DISCOVERY FOR YOUNG... NATURAL IMMUNOSUPPRESSION UNDERNUTRITION MAY BE GOOD... THE MYSTERIES OF HIV... SUMMARY REFERENCES

 
Common-Variable Immunodeficiency and HIV
Particularly intriguing are the reports of the reversal of common variable immunodeficiency (CVID) after HIV infection.^72–75 This primary immunodeficiency is characterized by onset after age 10 of recurrent infections, low immunoglobulin levels, and weak or absent antibody responses. Unlike congenital XLA, B cells, the precursors of plasma cells, are present (but nonfunctional) in CVID.

Wright et al in 1982 reported a gay man who developed CVID at age 24 and became infected with HIV at age 30. Two years later his previously low immunoglobulin levels normalized, and specific antibody production was restored.⁷² Three other similar cases have been recorded.^73–75

Although B-cell activation and hypergammaglobulinemia are common in HIV infection, the exact mechanism by which antibody production is corrected in CVID is not known. Its elucidation may identify a B-cell stimulant for some patients with CVID.

The CCR32 Mutation
As noted above, a chemokine receptor mutation may have provided a survival advantage for the black plague.¹⁸ The CCR chemokine receptor is the co-receptor for monocytotrophic HIV, and individuals with a homozygous mutation of CCR-32 are completely resistant to HIV infection, whereas heterozygotes for the mutation have a slower progression of disease.⁷⁶ Thus, multiexposed prostitutes and multitransfused hemophiliacs homozygous for the mutation do not become infected.^77,78 Based on these observations, blocking the CCR attachment site by using a natural ligand such as RANTES (regulated upon activation, normal T cells expressed and secreted) or monoclonal antibodies may prevent infection after needle-stick or sexual exposure.

HIV-2
HIV-2 infection is a milder form of HIV endemic in several West African countries such as Senegal and Gambia.⁷⁹ HIV-2 shares a 50% genetic homology with HIV-1 and similar routes of transmission.

HIV-2 infection may provide some protection to HIV-1 infection or slow its progression,⁸⁰ possibly by the presence of cross-reactive neutralizing antibodies or cytotoxic T lymphocytes, down-regulation of the CCR co-receptor, or high levels of ß chemokines.^81,82

The weak protection provided by HIV-2 and its morbidity excludes deliberate infection as a therapeutic option but indicates that cross-resistance develops among HIV-related retroviruses.

GB Virus Type C
GB virus type C (GBV-C), a variant strain of hepatitis G related to hepatitis C, provides significant protection against HIV-1. Discovered in 1995 in patients with hepatitis G, GBV-C is acquired by sexual transmission, by blood transfusion, or vertically from an infected mother.⁸³

Similar to hepatitis C, GBV-C infection is common in HIV-positive individuals (up to 20%) and in injection-drug users (up to 40%). Unlike hepatitis C, it does not cause hepatitis or any other as-yet-identified disease.⁸³ In this regard, it is similar to Torque teno virus, another chronic viral infection that has no clinical manifestations.⁸⁴

Several studies indicate that patients with HIV who are co-infected with GBV-C have less severe HIV disease and improved survival.^85–90 For example, Williams et al⁹⁰ report that men who were viremic with GBV-C were 2.8 times less likely to die 5 to 6 years after HIV seroconversion than those with persistent GBV-C viremia. Protection by GBV-C wanes when viremia disappears, thus excluding it as a vaccine candidate.

The mechanisms for the protective effect of GBV-C may involve modulation of co-receptor expression, enhanced cytotoxicity, or activation of innate immunity.⁸³ Different genotypes of GBV-C may exert distinct and varied effects on HIV replication, based on differing tissue and cellular tropisms. Exploitation of this viral interference may yield novel therapeutic approaches.^91,92

	SUMMARY

TOP ABSTRACT EDWARD JENNER AND VACCINATION THE HETEROZYGOTE ADVANTAGE RECEPTOR-DEFICIENCY PROTECTION DRUG DISCOVERY FOR YOUNG... NATURAL IMMUNOSUPPRESSION UNDERNUTRITION MAY BE GOOD... THE MYSTERIES OF HIV... SUMMARY REFERENCES

 
Some diseases modify or prevent another disease. Clinical observations of these interactions have led to the discovery of vaccines, therapeutic antibodies, drugs, and special diets. Patients with one form of agammaglobulinemia (XLA) never get EBV infections, whereas patients with another form (common variable) are seemingly cured of their antibody deficiency by HIV infection (treatment not recommended!). Genetic polymorphisms, symptomatic and asymptomatic, may prevent or modify the severity of infections, including bubonic plague, tuberculosis, secretory diarrhea, malaria, Parvovirus B19, and HIV. Jenner used cowpox to control smallpox and introduced the power of vaccines. Perhaps viral interference, using retroviruses similar to HIV-2 or hepatitis virus strains similar to GBV-C, should be explored as a means to combat HIV-1.

	FOOTNOTES

 
Accepted Mar 30, 2005.

Address correspondence to E. Richard Stiehm, MD, Mattel Children's Hospital at UCLA, 22–387 MDCC, Los Angeles, CA 90095. E-mail: estiehm{at}mednet.ucla.edu

The author has indicated he has no financial relationships relevant to this article to disclose.

	REFERENCES

TOP ABSTRACT EDWARD JENNER AND VACCINATION THE HETEROZYGOTE ADVANTAGE RECEPTOR-DEFICIENCY PROTECTION DRUG DISCOVERY FOR YOUNG... NATURAL IMMUNOSUPPRESSION UNDERNUTRITION MAY BE GOOD... THE MYSTERIES OF HIV... SUMMARY REFERENCES

 

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