Normally, when you breathe in an irritant or are subjected to a stressor such as exercise, your airways relax and open, allowing the lungs to get rid of irritants or take in more air. In a person with asthma, muscles in the airways tighten and the lining of the air passages swells. The immune system gets involved, but instead of helping, it causes inflammation.
Asthma is a disease of both adults and children. In fact, asthma is the most common chronic childhood illness. About half of all cases of asthma develop before the age of 10. Many children with asthma also have allergies. While there is no cure for asthma, it can be controlled.
Asthma Signs and Symptoms
Most people with asthma have periodic attacks separated by symptom-free periods. Some asthmatics have chronic shortness of breath with episodes of increased shortness of breath. Asthma attacks can last minutes to days and can become dangerous if the airflow becomes severely restricted.
The primary symptoms of asthma include:
- Shortness of breath
- Wheezing -- usually begins suddenly; may be worse at night or early in the morning; aggravated by exposure to cold air, exercise, heartburn and relieved with the use of bronchodilators (drugs that open the airways; see Medications)
- Chest tightness
- Cough (dry or with sputum) -- sometimes this is the only symptom
Call for emergency assistance if you have or are with someone having any of these serious symptoms:
- Extreme difficulty breathing or cessation of breathing
- Bluish color to the lips and face (called cyanosis)
- Severe anxiety
- Rapid pulse
- Profuse sweating
- Decreased level of consciousness (such as drowsiness or confusion)
Additional symptoms that may be associated with an asthma attack include:
- Flared nostrils
- Abnormal breathing pattern, in which exhalation takes more than twice as long as inhalation
- Use of the muscles between the ribs (called intercostals) to help with the increased work of breathing
- Coughing up blood (called hemoptysis)
Asthma is most likely caused by a combination of several factors. Experts suggest that in people who are susceptible (genetically predisposed), factors such as allergens (substances that commonly induce an allergic reaction), infections, dietary patterns, exercise, cigarette smoke, and stress can bring on an asthma attack.
The following factors may increase the risk of developing asthma:
- Allergies -- children with asthma often have allergies as well
- Family history of asthma or allergies
- Cigarette smoke, including second hand smoke from, for example, parents or a spouse
- Food allergies - a true food allergy, particularly one that induces asthma, is difficult to identify and, therefore, it is not clear exactly how frequently (or infrequently) this contributes to asthma; it seems to be more common in children than in adults and the responsible foods include eggs, milk, wheat, soy, peanuts, fish, shellfish, and sulfite food perservatives.
- Living in a Western or industrialized country - some experts believe that dietary habits (more processed foods, less fruits and vegetables), indoor living (resulting in overexposure to indoor allergens), energy- efficient homes (trapping allergenic dust mites inside), immunizations, and possibly, declining rates of breastfeeding contribute to the rising rates of asthma
- Urban living
- Gender -- among younger children, asthma develops twice as frequently in boys as in girls, but after puberty it may be more common in girls
- Obesity - controversial; a recent study suggests that asthma is over-diagnosed among obese people
Childhood asthma in particular can be triggered by almost all of the same things that trigger allergies, such as the following:
- Sensitivity to allergens in the air, such as dust, cockroach waste, animal dander, indoor and outdoor mold, pollens
- Respiratory infections
- Air pollutants, such as smoke from tobacco or a fireplace, aerosols, perfumes, fresh newsprint, diesel particles, sulfur dioxide, elevated ozone levels, and fumes from paint, cleaning products, and gas stoves
- Changes in the weather, especially in temperature (particularly cold) and humidity
Other triggers include:
- Behaviors that affect breathing (exercising, laughing, crying, yelling)
The symptoms of asthma can mimic several other conditions, and a doctor must take a thorough history to rule out other diseases. Questions will likely be asked about how and when symptoms occur, and if there is a family history of allergies and asthma or occupational exposure to chemicals. If asthma is suspected, tests (called pulmonary function tests) will probably be done to measure, among other things, the volume of your lungs and how much air you exhale. Other tests may include chest and sinus x-rays, blood tests, or allergy tests.
Preventive Care for Asthma
Although there is no method guaranteed to prevent asthma, there are a number of measures parents can take to reduce their child's risk of developing asthma. These include:
- Exclusively breastfeeding for the first 3 to 6 months of life; this issue is controversial, however, with the most recent (and largest) study suggesting that breastfeeding for the first 6 months of life helps to protect the child.
- Delaying the introduction of solid food until age 6 months
- Manipulating the child's environment (not smoking during pregnancy or around infants, eliminating household allergens such as mites and cockroaches. For example, to reduce exposure to dust mites, encase mattresses and pillows in special covers that are impermeable to allergens; also, remove carpets from bedrooms.)
According to certain studies on adults, apples and selenium-rich food in the diet may protect against asthma, and moderate consumption of red wine may be associated with less severe asthma attacks. These foods are high in antioxidants (namely, flavonoids). It is too early to say definitively that these nutrients protect against asthma, however. Plus, it is important to note that in certain individuals, red wine may actually induce asthma symptoms if you have an allergy to sulfites, a food additive, or any other substance found in wine. Often, wine labels indicate if sulfites are present.
Key steps in preventing asthma attacks include identifying the allergens and the triggers that bring on or worsen your asthma symptoms and then working to eliminate or avoid them. Sometimes it takes exposure to more than one of these factors before an asthma episode is triggered. Keeping a diary to determine triggers may be helpful.
The following conditions are common triggers for asthma. Reduce your chances of exposure to them by taking some common-sense steps:
- Viral infections (colds, flu, bronchitis, pneumonia) - stay away from people who you know are ill
- Sinusitis and allergic rhinitis (hay fever or year-round allergies) - avoid seasonal allergens by staying indoors in air conditioning as much as possible and eliminating indoor allergens; fewer allergy attacks generally means fewer cases of sinusitis and asthma
- Gastroesophageal reflux (heartburn) - avoid provoking foods, medication, and mealtime habits
Avoid the following altogether:
- If sensitive or allergic, aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs)
- Beta-blockers (such as acebutolol, atenolol, esmolol, labetalol, metoprolol, nadolol, pindolol, propranolol, and timolol) including those in eye medication
- If sensitive or allergic, processed potatoes, shrimp, dried fruit, beer, and wine - these often contain sulfite food preservatives
Allergy desensitization, if you have a known allergy, may decrease the number of asthma attacks you experience, diminish the intensity of each attack, and lower the amount of medication that you need.
Asthma Treatment Approach
Avoiding asthma attacks, reducing inflammation, and preventing lung damage are the primary goals of treatment. This requires educating yourself about asthma, working closely with your doctor to determine the severity of your asthma and to define a treatment plan, and following recommendations. Adjusting your environment as much as possible to prevent exposure to allergens or irritants are important for the successful control of asthma. Certain nutritional changes, particularly increasing the amount of omega-3 fatty acids in your diet and decreasing omega-6 fatty acids, and acupuncture may be useful adjuncts.
- Quit smoking
- Lose weight if you are overweight and already have asthma; although the connection between obesity and asthma is not entirely understood, excess weight may put pressure on the lungs and trigger an inflammatory response.
- Keep a diary of respiratory complaints - this may help determine triggers.
Asthma Nutrition and Dietary Supplements
Studies indicate that people with asthma tend to have low levels of certain nutrients (for example, selenium and potassium) and that the Western diet (high in fast foods and low in fresh fruits and vegetables) has been associated with higher rates of asthma. In fact, fried foods and margarine may be particularly bad, especially in children. On the other hand, it has been suggested that adding onion, garlic, pungent spices, and antioxidants (such as foods rich in vitamin C, vitamin E, flavonoids, and beta-carotene) to the diet may help reduce symptoms.
Two large studies found that low dietary magnesium intake may be associated with risk of developing asthma in both children and adults.
A review of scientific studies suggests that N-acetylcysteine may help dissolve mucus and improve symptoms associated with asthma.
Omega-3 Fatty Acids
Preliminary research on adults with asthma suggests that an omega-3 fatty acid supplement may reduce inflammation and improve lung function.
One thing that can be said about omega-3 fatty acids is that if you enrich your diet with this type of essential fatty acid (from foods such as cold-water fish, flaxseeds, pumpkin seeds, and walnuts) and reduce your intake of omega-6 fatty acids (from foods like meat, egg yolks, and certain cooking oils), this is likely to help improve your symptoms.
Data from several studies suggest that compared to diets with normal amounts of potassium, diets low in potassium are associated with poor lung function and even asthma in children. Improving dietary intake of potassium through foods such as fish, fruits, and vegetables may therefore be valuable for preventing or treating asthma. Adequate amounts of magnesium are needed to maintain normal levels of potassium. In addition, the drug theophylline (used sometimes for asthma) may deplete potassium, as can excessive intake of salt or caffeine in the diet.
Quercetin, which is a member of a group of antioxidants called flavonoids, inhibits the production and release of histamine and other allergic/inflammatory substances. Histamine is a substance that contributes to allergy symptoms such as a runny nose, watery eyes, and hives. Like other flavonoids, quercetin is a plant pigment responsible for colors seen in fruits and vegetables.
Studies suggest that people with asthma tend to have low blood levels of selenium. In addition, a population-based study (studies that evaluate groups of people) suggested that eating selenium-rich foods may have a protective effect against asthma. Plus, taking selenium supplements may prove to be helpful as well. In a study of 24 people with asthma, for example, those who received selenium supplements for 14 weeks demonstrated a significant improvement in symptoms compared to those who received placebo. More studies, with larger numbers of people and lasting longer than 14 weeks, are needed to determine whether selenium supplementation is truly safe and effective for people with asthma.
Although research is limited, there is some indication that vitamin C, particularly from fresh fruit in your diet, may be useful for treating allergy-related conditions such as asthma.
Other supplements that may have benefit for asthma include:
- Coenzyme Q 10 (CoQ10) - if you have asthma, you may have low levels of this antioxidant in your blood. It is not known at this time, however, whether taking CoQ10 supplements will make any difference in your symptoms.
- Lactobacillus acidophilus - there is some evidence that this "good" organism (called a probiotic), which is found naturally in the gut, may reduce the risk of developing an allergic reaction, including asthma. In fact, some early evidence suggests that if mothers who have at least one relative with asthma, or some other allergy-related illness, take this probiotic while pregnant and breastfeeding, their babies may be less likely to develop asthma.
- Lycopene and beta-carotene - preliminary data suggests that each of these two antioxidants may prove useful for preventing exercise induced asthma symptoms when taken daily.
- Vitamin B6 - may be needed if you are taking theophylline because this medication can lower blood levels of this nutrient.
Asthma Suggested Nutritional Supplementation
- D-43 Bronchasthmol - 10-15 drops under tongue 3 times daily. Acute: 5 - 10 drops under tongue every 20 - 30 minutes.
- 500-C Methoxyflavone - 3 tablets initially, then 1 tablet every 20-30 minutes until symptoms subside. 500-C Methoxyflavone is a synergistic formula that features a specialized complex of bioflavonoids combined with vitamin C.
- Vitamin C and the bioflavonoids are known to be helpful in reducing the effects of allergy mediated bronchial asthma, sometimes stopping the attack in as little as five minutes.
- Nazanol -1-2 tablets 2-3 times daily on empty stomach.
Natural , stimulant-free herbal support for healthy sinus, nasal and lung function.
- DMG Sublingual - 1 tablet under tongue every 20-30 minutes until symptoms subside.
- Research has shown DMG to be a physiologically active ingredient that: 1) is an anti-stress agent that can significantly improve physical and mental performance; 2) can improve and stimulate oxygen utilization and thereby reduce hypoxic (low oxygen) states in the body; and 3) can increase resistance to disease and infection by strengthening both arms of the immune response system, including antibody and lymphocyte production.
- Mega B12 / Folic - 4 drops three times daily
Highly concentrated B12/folic acid liquid
- NOTE: Childhood asthma has been shown to respond remarkably well to B12 therapy.
- VentiMax - Adults: 2 capsules twice daily with meals. Children over 6 years: 1 capsule twice daily with meals. Children under 6 years: Use VentiMax PD
VentiMax is the only scientifically designed nutritional supplement for asthma free of hidden herbal stimulants such as caffeine, theophylline, and ephedrine.
- VentiMax PD - Children 1-3 years: 1-2 teaspoons twice daily mixed in apple or pear juice. Children 4-6 years: 1 Tablespoon twice daily mixed in apple or pear juice.
- PerimineTM - 1-2 tablets twice daily with food.
Patented, Flavonoid-Rich Perilla Seed Extract.
In severe chronic asthma, Dr. Jeffrey Bland recommends adding
- UltraInflamX Plus 360 - 2 scoops twice daily
Multi-mechanistic support with key nutrients, phytonutrients, and selective kinase response modulators (SKRMs) to address underlying inflammation.
Asthma Dietary Suggestions
- Anti-Inflammatory Diet
Asthma Supporting Research
1. Aligne CA, Auinger P, Byrd RS, Weitzman M. Risk factors for pediatric asthma. Contributions of poverty, race, and urban residence. Am J Respir Crit Care Med. 2000;162(3 Pt 1):873-877.
2. American College of Allergy, Asthma and Immunology. Accessed athttp://www.allergy.mcg.edu/patients/control.html on July 22, 2002.
3. Balon J, Aker PD, Crowther ER, et al. A comparison of active and simulated chiropractic manipulation as adjunctive treatment for childhood asthma. N Engl J Med. 1998;339:1013-1020.
4. Birkel DA, Edgren L. Hatha yoga: improved vital capacity of college students. Altern Ther Health Med. 2000;6(6):55-63.
5. Bronfort G, Evans RL, Kubic P, Filkin P. Chronic pediatric asthma and chiropractic spinal manipulation: a prospective clinical series and randomized clinical pilot study. J Manipulative Physiol Ther. 2001;24(6):369-377.
6. Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr. 1999;69(6):1086-1107.
7. Ciarallo L, Brousseau D, Reinert S. Higher-dose intravenous magnesium therapy for children with moderate to severe acute asthma. Arch Ped Adol Med. 2000;154(10):979-983.
8. Ciarallo L, Sauer AH, Shannon MW. Intravenous magnesium therapy for moderate to severe pediatric asthma: results of a randomized, placebo-controlled trial.
9. J Pediatr. 1996;129(6):809-814.
10. Cummings S, Ullman D. Everybody's Guide to Homeopathic Medicines. 3rd ed. New York, NY: Penguin Putnam; 1997: 237-238.
11. Ernst E. Breathing techniques - adjunctive treatment modalities for asthma? A systematic review. Eur Respir J. 2000;15(5):969-972.
12. Field T, Henteleff T, Hernandez-Reif M, et al. Children with asthma have improved pulmonary functions after massage therapy. J Pediatr. 1998;132(50:854-858.
13. Fung KP, Chow OKW, So SY. Attentuation of exercise-induced asthma by acupuncture. Lancet. 1986;2(8521-8522): 1419-1421.
14. Gazdol F, Gvozdjakova A, Nadvornikova R, et al. Decreased levels of coenzyme Q(10) in patients with bronchial asthma. Allergy. 2002;57(9):811-814.
15. Gdalevich M, Mimouni D, Mimouni M. Breast-feeding and the risk of bronchial asthma in childhood: a systematic review with meta-analysis of prospective studies. J Pediatr. 2001;139(2):261-266.
16. Gilliland FD, Berhane KT, Li YF, Kim DH, Margolis HG. Dietary magnesium, potassium, sodium, and children's lung funtion. Am J Epidemiol. 2002. 15;155(2):125-131.
17. Graham RI, Pistolese RA. An impairment rating analysis of asthmatic children under chiropractic care. J Vertebr Sublux Res.1997;1(4):41-48.
18. Gupta I, Gupta V, Parihar A, et al. Effects of Boswellia serrata gum resin in patients with bronchial asthma: results of a double-blind, placebo-controlled, 6-week clinical study. Eur J Medical Research. 1998;3(11):511-514.
19. Haby MM, Peat JK, Marks GB, Woolcock AJ, Leeder SR. Asthma in preschool children: prevalence and risk factors. Thorax. 2001;56(8):589-595.
20. Hackman RM, Stern JS, Gershwin ME. Hypnosis and asthma: a critical review. J Asthma. 2000;37(1):1-15.
21. Hasselmark L, Malmgren R, Zetterstrom O, Onge G. Selenium supplementation in intrinsic asthma. Allergy. 1993;48:30-36.
22. Hijazi N, Abalkhail B, Seaton A. Diet and childhood asthma in a society in transition: a study in urban and rural Saudi Arabia. Thorax. 2000;55:775-779.
23. Hondras MA, Linde K, Jones AP. Manual therapy for asthma (Cochrane Review). Cochrane Database Syst Rev. 2001;(1):CD001002.
24. Hope BE, Massey DB, Fournier-Massey G. Hawaiian materia medica for asthma. Hawaii Med J. 1993;52:160-166.
25. Howes LG. Which drugs affect potassium? Drug Saf. 1995;12(4):240-244.
26. Huntley A, White AR, Ernst E. Relaxation therapies for asthma: a systematic review. Thorax. 2002;57(20:127-131.
27. Jain SC, Rai L, Valecha A, Jha UK, Bhatnagar SO, Ram K. Effect of yoga training on exercise tolerance in adolescents with childhood asthma. J Asthma. 1991;28(6):437-442.
28. Joos S, Schott C, Zou H, Daniel V, Martin E. Immunomodulatory effects of acupuncture in the treatment of allergic asthma: a randomized controlled study. J Alt Comp Med. 2000;6(6), 519-525.
29. Kadrabova J, Mad'aric A, Kovacikova Z, Podivinsky F, Ginter E, Gazdik F. Selenium status is decreased in patients with intrinsic asthma. Biol Trace Elem Res. 1996;52(3):241-248.
30. Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: a randomized placebo controlled trial. Lancet. 2001;357(9262):1076-1079.
31. Kaur B, Rowe BH, Ram FS. Vitamin C supplementation for asthma (Cochrane Review). Cochrane Databse Syst Rev. 2001;4:CD000993.
32. Kleijnen J, ter Riet G, Knipschild P. Acupuncture and asthma: a review of controlled trials. Thorax. 1991;46:799-802.
33. Kohen DP, Wynne E. Applying hypnosis in a preschool family asthma education program; uses of storytelling, imagery, and relaxation. Am J Clin Hypnosis. 1997;39(3):169-181.
34. Kruzel T. The Homeopathic Emergency Guide. Berkeley, Calif: North Atlantic Books; 1992:21-27.
35. Lehrer P. Emotionally triggered asthma: a review of research literature and some hypotheses of self-regulation therapies. Appl Psychophysiol Biofeedback. 1998;23(1):13-41.
36. Lehrer P, Feldman J, Giardino N, Song HS, Schmaling K. Psychological aspects of asthma. J Consult Clin Psychol. 2002;70(3):691-711.
37. Levine M, Rumsey SC, Daruwala R, Park JB, Wang Y. Criteria and recommendations for vitamin C intake. JAMA. 1999;281(15):1415-1453.
38. Linde, K, Jobst K, Panton J. Acupuncture for chronic asthma (Cochrane Review). In: The Cochrane Library, Issue 3, 2001. Oxford: Update Software.
39. Mazur LJ, De Ybarrondo L, Miller J, Colasurdo G. Use of alternative and complementary therapies for pediatric asthma. Tex Med. 2001;97(6):64-68.
40. Meydani SN, Ha WK. Immunologic effects of yogurt. Am J Clin Nutr. 2000;71(4):861-872.
41. Middleton E, ed. Allergy: Principles and Practice. 5th ed. St. Louis, Mo: Mosby-Year Book, Inc; 1998.
42. Miller AL. The etiologies, pathophysiology, and alternative/complementary treatment of asthma. Altern Med Rev. 2001;6(1):20-47.
43. Monteleone CA, Sherman AR. Nutrition and asthma. Arch Intern Med. 1997;157:23-24.
44. Nagakura T, Matsuda S, Shichijyo K, Sugimoto H, Hata K. Dietary supplementation with fish oil rich in omega-3 polyunsaturated fatty acids in children
45. with bronchial asthma. Eur Resp J. 2000;16(5):861-865.
46. Neuman I, Nahum H, Ben-Amotz A. Prevention of exercise-induced asthma by a natural isomer mixture of beta-carotene. Ann Allergy Asthma Immunol. 1999;82(6):549-553.
47. Neuman I, Nahum H, Ben-Amotz A. Reduction of exercise-induced asthma oxidative stress by lycopene, a natural antioxidant. Allergy. 2000;55(12):1184-1189.
48. Newnham DM. Asthma medications and their potential adverse effects in the elderly: recommendations for prescribing. Drug Saf. 2001;24(14):1065-1080.
49. NIH Consensus Statement: Acupuncture. National Institutes of Health, Office of the Director. 1997;15(5):1-34. Accessed athttp://odp.od.nih.gov/consensus/cons/107/107_statement.htm on September 24, 2001.
50. Nielsen NH, Bronfort G, Bendix T, Madsen F, Weeke B. Chronic asthma and chiropractic spinal manipulation: a randomized clinical trial. Clin Exp Allergy. 1995;25:80-88.
51. Okamoto M, Misunobu F, Ashida K, Mifune T, Hosaki Y, Tsugeno H et al. Effects of dietary supplementation with n-3 fatty acids compared with n-6 fatty acids on bronchial asthma. Int Med. 2000;39(2):107-111.
52. Okamoto M, Misunobu F, Ashida K, et al. Effects of perilla seed oil supplementation on leukotriene generation by leucocytes in patients with asthma associated with lipometabolism. Int Arch Allergy Immunol. 2000;122(2):137-142.
53. Rohdewald P. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther. 2002;40(4):158-168.
54. Romieu I, Trenga C. Diet and obstructive lung diseases. Epidemiol Rev. 2001;23(2):268-287.
55. Rowe BH, Edmonds ML, Spooner CH, Camargo CA. Evidence-based treatments for acute asthma. [Review]. Respir Care. 2001;46(12):1380-1390.
56. Sancier KM. Therapeutic benefits of qigong exercises in combination with drugs. J Altern Complement Med. 1999;5(4):383-389.
57. Sanders R. Pine bark extract is a potent antioxidant, and may help boost the effects of vitamin C and other antioxidants, UC Berkeley scientists report [news release]. February 5, 1998. Accessed athttp://www.berkeley.edu/news/media/releases/98legacy/02_05_98a.html on July 19, 2002.
58. Sathyaprabha TN, Murthy H, Murthy BT. Efficacy of naturopathy and yoga in bronchial asthma - a self controlled matched scientific study. Ind J Physiol Pharmacol. 2001;45(10:80-86.
59. Shaheen SO, Sterne JA, Thompson RL, Songhurst CE, Margetts BM, Burney PG. Dietary antioxidants and asthma in adults: population-based case-control study. Am J Respir Crit Care Med. 2001;164(10 Pt 1):1823-1828.
60. Shimizu T, Maeda S, Arakawa H, et al. Relation between theophylline and circulating vitamin levels in children with asthma. Pharmacol. 1996;53:384-389.
61. Smit HA, Grievink L, Tabak C. Dietary influences on chronic obstructive lung disease and asthma: a review of the epidemiological evidence. Proc Nutr Soc. 1999;58(2):309-319.
62. Tamaoki J, Nakata J, Kawatani K, Tagaya E, Nagai A. Ginsenoside-induced relaxation of human bronchial smooth muscle via release of nitric oxide. Br J Pharmacol. 2000;130(8):1859-1864
63. Ullman D. Homeopathic Medicine for Children and Infants. New York, NY: Penguin Putnam; 1992: 46-48.
64. Ullman D. The Consumer's Guide to Homeopathy. New York, NY: Penguin Putnam; 1995: 260-261.
65. Urata Y, Yoshida S, Irie Y, et al. Treatment of asthma patients with herbal medicine TJ-96: a randomized controlled trial. Respir Med. 2002 Jun;96(6):469-474.
66. Vally H, Carr A, El-Saleh J, Thompson P. Wine-induced asthma: a placebo-controlled assessment of its pathogenesis. J Allergy Clin Immunol. 1999;103(1 Pt 1):41-46.
67. Vedanthan PK, Kesavalu LN, Murthy KC, et al. Clinical study of yoga techniques in university students with asthma: a controlled study. Allergy Asthma Proc. 1998;19(1):3-9.
68. Yoshida S. Herbalism for the treatment of asthma. Chest. 1999;116(2):582-583.
69. Ziment I, Tashkin DP. Alternative medicine for allergy and asthma. J Allergy Clin Immunol. 2000;106(4):603-614.