Rat urine proteins

  • Allergen search puff

    SEARCH FOR ALLERGENS

    Search ImmunoCAP allergens and allergen components. Note that all information is in English.

Code: e74
Latin name: Rattus norvegicus
Source material: Urine
Family: Muridae
Common names: Rat, Brown rat, House rat, Norway rat
Selective breeding in this species has produced the albino Laboratory Rat, widely used for medical and other research purposes.
 
House Rats comprise two species, Rattus norvegicus, the Brown or Norway Rat, and Rattus Rattus, the Black or Alexandrine Rat, which also originated in Asia, spread worldwide by ships, and is a well-known disease carrier, but has been largely displaced in cooler regions by the Brown Rat. They are roughly similar in appearance and habits. (The Brown Rat is larger, but with a shorter tail and smaller ears, while the dark-grey Black Rat is a better climber.)
 
Besides the House Rats, the genus Rattus contains several hundred wild-living species. In addition, many other members of the order Rodentia are called Rats: e.g., the Bandicoot Rat, the Wood or Pack Rat, the Rice Rat, the Muskrat, and the Kangaroo Rat. See also Mouse.

Direct or indirect contact with animal allergens frequently causes sensitisation. '
 
Animal allergens are major components of house and laboratory dust.

Allergen Exposure

Geographical distribution
This species of Rat is not a native of Norway, as its name suggests. The species originated in Asia, reached Europe early in the eighteenth century and arrived in North America about 1775 on ships from England. Its distribution is now worldwide.
 
Many consider this Rat to be the greatest mammal pest of all time. It has caused more deaths than all the wars in history. It harbours lice and fleas and has been the source of bubonic plague, typhus, trichina, tularemia, infectious jaundice and other serious diseases. These Rats are usually a contributing factor of first importance in the spread of pandemics during war. They also cause considerable depletion and pollution of human food stores, and damage to buildings and their contents from destructive chewing of wiring, pipes, and walls. But despite human efforts to exterminate Rats, the House Rat population is probably equal to the human population.
 
The Brown Rat grows up to 25 cm long excluding the naked, scaly tail, and sometimes weighs more than half a kilogram. It is commonly brown with whitish underparts and pink ears, feet, and tail. It breeds, and therefore aggressively forages, all year round.
 
Environment
As small, intelligent, bold, prolifically breeding omnivores, nesting in practically any sort of disused cavity or burrowing in the ground, and adept at swimming, jumping and climbing, Brown Rats are highly adaptable and live in a great variety of environments. They may hide in huge numbers in and around human dwellings, especially in cities, towns and their surroundings, There, they live principally in basements, on the ground floor, in subways, and in burrows under sidewalks or outbuildings. They are also frequently found in cultivated fields, grain storage facilities, livestock housing and garbage dumps. Basically, they are at home wherever there is a food source and sufficient cover from predators, and this includes some unexpected places like the salt marshes of the US Atlantic coast, where edible flotsam is washed up on the beaches.
 
Especially because of the numbers of Rats used in laboratories, allergy to Rats is an important occupational health problem.
 
Unexpected exposure
Most exposure to Brown Rats is unexpected. These secretive, mainly nocturnal animals pass unseen in more or less regular scavenging journeys over a variety of surfaces with which humans have daily contact. Their skin flakes, urine, feces, and saliva are left behind. They have also been known to bite sleepers.
 
Allergens
Allergens characterised to date include:
  • Rat n 1, a 17 kDa protein (1-3, 25)
     
  • Rat n 1.01
     
  • Rat n 1.02, a major allergen, a 17 kd protein (also called alpha 2u-globulin)
     
  • Rat n 1A (previously known as Ag4), a 20-21 kDa protein, and Rat n 1B (previously known as Ag13), a 16-17 kDa sized protein, are both variants of the same protein. These allergens are found in hair, dander, urine and saliva (3-5). Rat n 1A is a prealbumin. Rat n 1B is an alpha-2-eu-globulin and primarily a male Rat allergen (5).
Rat n 1.01 and Rat n 1.02 are lipocalins (lipocalin-pheromone binding proteins) (6).
 
Rat urine has been identified as a major source of the allergens in laboratory animal allergy. The age and sex of the Rat can influence the allergenic composition of the urine (7, 25). Male rodents excrete higher levels of urinary allergens than female rodents (8). Rat and mouse urinary allergens are mainly present as large particles (>5.8 microm) (9).
 
Rodents have permanent proteinuria, and thus the allergen is constantly present in their urine. They spray urine on their surroundings, where the proteins dry up and become airborne on dust particles.
 
Some of the minor allergens are those antigens which appear to be unique to urine, saliva or the skin, suggesting that sensitisation to Rats can result from exposure to allergenic material from any of these 3 sources. Significant concentrations of airborne rodent allergens have been measured in both laboratories and apartments in inner cities (10-14).
 
Also isolated from Rat urine are 75 kDa and 68 kDa serum protein allergens, the former probably serum albumin and the latter probably transferrin (15). The prevalence of specific IgE in Rat-allergic patients to the 68 kDa (albumin) allergen is between 24% and 28.9% (16-18).
 
Prealbumin and alpha(2)-euglobulin (as these were previously termed), detected in Rat urine, are highly homologous and have now been identified as alpha(2)-globulin species. The "prealbumin" fraction corresponds to alpha(2u)-globulin originating from the salivary gland, and the "alpha(2)-euglobulin" fraction has been shown to be identical to the major urinary protein (MUP) or alpha(2u)-globulin. The two major protein fractions of Rat urine thus appear to constitute different forms of the same parent protein, alpha(2u)-globulin. These allergens are found mainly in adult male Rats. Rat n 1B is produced in the liver, where it is androgen-dependant, and in the salivary, mammary and other exocrine glands, where its production is not androgen dependant (6).
 
The number of Rats, Rats' bedding, cage design, and stock density influence the level of aeroallergen concentration and exposure (19). Rat allergen can also be carried on clothes or by wind to distant sites, with traces of Rat urinary aeroallergens measured in tea rooms inside and near offices outside the animal housing (20-21).
 
The highest airborne Mouse allergen levels have been measured during manual emptying of cages, during changing of cages on an unventilated table, and during handling of male animals on an unventilated table. Using ventilated cage-changing wagons has been shown to reduce the allergen exposure level from 77 to 17 ng/m3 (22). Similar results can be expected with Rats. Airborne Rat allergens are particles ranging from 1 to 20 micrometres in size, and can remain airborne for 60 minutes or more after disturbance. Rat allergen exposure levels less than 0.7 microg/m3 appear not to be associated with an increased risk of occupational asthma (23). More intense exposure to airborne Rat n 1 and endotoxin occurs not only during cleaning, but also during feeding tasks, probably because the allergens become airborne during the disturbance (24).
 
Rat dust is a complex allergenic source and contains allergens from Rats' urine, epithelium and saliva. Fur is the most probable source of the high-molecular-weight allergens found in Rat room dust (7, 25). 
The 17 kDa dust allergen has immunological identity with Rat n 1 and is a suitable marker protein for the quantification of airborne Rat allergen (25).

Potential Cross-Reactivity

In IgE immunoblot inhibition studies and histamine release tests, it has been demonstrated that patients who react to Dog albumin exhibit IgE reactivity with purified albumins from Cat, Mouse, Chicken, and Rat. Significant sequence homologies have been demonstrated with albumins from different species: Human: 82.6%, Pig: 81.8%, Cattle: 77.3%, Sheep: 78.8%, Mouse: 75.8%, and Rat: 76.2% (26).
 
Practically all respiratory animal allergens, including Rat, characterised at the molecular level belong to the lipocalin family of proteins. Examples are the major allergens of Horse, Cow, Dog, Mouse and Cockroach as well as beta-lactoglobulin of Cow's milk (27). A certain degree of cross-reactivity is thus possible.

Clinical Experience

IgE mediated reactions
Rat allergens found in dust, urine, epithelium and saliva are a frequent cause of asthma, allergic rhinitis and allergic conjunctivitis, mainly in laboratory workers but also in ordinary individuals (28-30).
 
There is a strong association between work-related symptoms and specific sensitisation (31). Workers exposed to laboratory animals are at risk of developing asthma, rhinitis, angioedema, conjunctivitis, and urticaria. Between 10% and 33% of scientists and technicians handling small animals will develop laboratory animal allergy symptoms within 3 years of employment. Many of them will have severe symptoms requiring a change of occupation (9, 25, 32-33).
 
In workers exposed to Rats, Rat urinary allergen sensitisation risk increased with increasing exposure intensity. Workers who were atopic had a clearly elevated sensitisation risk at low allergen exposure levels (34). In a cross-sectional study performed on 540 workers at 8 facilities to quantify the exposure-response relationship for allergy to Rats, no clear exposure-response relationship was observed. However, in the group of workers with less than 4 years of working experience with laboratory animals, the prevalence rate of sensitisation to Rat allergens was clearly associated with exposure levels. The exposure-response relationship was steepest for workers with atopy-associated risk factors, i.e., self-reported allergy or sensitisation to Cats or Dogs, or elevated total serum IgE. The prevalence rates of sensitisation to Rat allergens for these workers were about 15, 9.5, and 7.3 times higher in the high-, medium-, and low-exposure group, respectively, compared with the internal reference group (35).
 
In a case-referent analysis of a cohort of 342 newly employed laboratory animal workers, examining the relationship between exposure to Rat urinary allergens, atopic status, smoking and the development of allergic symptoms and specific sensitisation, of those who developed illness, 80% reported that their symptoms started within 2 years of employment. The odds ratio for development of each symptom type (respiratory, eye or nose, and skin) and of an immediate skin-specific IgE positivity was increased in those with direct contact with Rats (36).
 
In a study evaluating the risk of laboratory animal allergy among research staff working in laboratories separate from the animal confinement area, 20% of the subjects had serum-specific IgE >0.35 kU/l to Rat urinary allergens and/or Mouse urinary allergens, and 32% had experienced animal work-related symptoms, although 90% of aeroallergen samples from the laboratories in question were below the detection limit. More than 4 years of exposure significantly increased laboratory animal sensitisation and symptoms. Working mainly with male rodents resulted in increased risk for sensitisation and for symptoms (8).
 
The suitability of radioallergosorbent test (RAST) inhibition to quantify occupational exposure to Rat urinary aeroallergen (RUA) has been assessed. The authors conclude that, in view of the complexity of Rat allergens, RAST inhibition is an appropriate method for the quantification of occupational exposure to Rats (37).
 
Compiled by Dr Harris Steinman, harris@zingsolutions.com

References

  1. Longbottom, J. L. Chracterization of allergens from the urines of experimental animals. McMillan Press, London 1983;525-529
  2. Laperche, Y., K. R. Lynch, K. P. Dolans, and P. Feigelsen. Tissue-specific control of alpha 2u globulin gene expression: constitutive synthesis in submaxillary gland. Cell 1983;32:453-460
  3. Bush RK, Wood RA, Eggleston PA. Laboratory animal allergy. J Allergy Clin Immunol 1998;102(1):99-112
  4. Spitzauer S. Allergy to mammalian proteins: at the borderline between foreign and self? Int Arch Allergy Immunol 1999;120(4):259-69
  5. Schou C. Defining allergens of mammalian origin. Clin Exp Allergy 1993;23:7-14
  6. Bayard C, Holmquist L, Vesterberg O. Purification and identification of allergenic alpha (2u)-globulin species of rat urine. Biochim Biophys Acta 1996;1290(2):129-34
  7. Gordon S, Tee RD, Stuart MC, Newman Taylor AJ. Analysis of allergens in rat fur and saliva. Allergy 2001;56(6):563-7
  8. Renstrom A, Karlsson AS, Malmberg P, Larsson PH, van Hage-Hamsten M. Working with male rodents may increase risk of allergy to laboratory animals. Allergy  2001;56(10):964-70
  9. Hollander A, Heederik D, Doekes G, Kromhout H. Determinants of airborne rat and mouse urinary allergen exposure. Scand J Work Environ Health  1998 Jun;24(3):228-35
  10. Walls AF, Longbottom JL. Quantitative immunoelectrophoretic analysis of rat allergen extracts. II. Fur, urine and saliva studied by crossed radio-immunoelectrophoresis. Allergy 1983;38(7):501-12
  11. Walls AF, Longbottom JL. Comparison of rat fur, urine, saliva, and other rat allergen extracts by skin testing, RAST, and RAST inhibition. J Allergy Clin Immunol 1985;75(2):242-51
  12. Twiggs JT, Agarwal MK, Dahlberg MJE, Yunginger JW. Immunochemical measurement of airborne mouse allergens in a laboratory facility. J Allergy Clin Immunol 1982;69:522-6
  13. Swanson MC, Agarwwal MK, Reed CE. An immunochemical approach to indoor aeroallergen quantitation with a new volumetric air sampler: studies with mite, roach, cat, mouse and guinea pig antigens. J Allergy Clin Immunol 1985;76:724-9
  14. Sakaguchi M, Inouye S, Miyazawa H, et al. Evaluation of countermeasures for reduction of mouse airborne allergens. Laboratory Animal Science 1990;40:613
  15. Gordon S, Tee RD, Taylor AJ. Analysis of rat serum allergens. J Allergy Clin Immunol 1997;99(5):716-7
  16. Gordon S, Tee RD, Newman Taylor AJ. Analysis of rat urine proteins and allergens by sodium dodecylsulfate-polyacrylamide gel eletrophoresis and immunoblotting. J Allergy Clin Immunol 1993;92:298-305
  17. Wahn U, Peters T, Siraganian RP. Studies on the allergenic significance and structure of rat serum albumin. J Immunol 1980;125:2544-9
  18. Wood RA. Laboratory animal allergens. ILAR J 2001;42(1):12-6
  19. Taylor AJ, Gordon S, Tee RD. Influence of bedding, cage design, and stock density on rat urinary aeroallergen levels. Am J Ind Med 1994;25(1):89
  20. Nieuwenhuijsen MJ, Gordon S, Tee RD, Venables KM, McDonald JC, Newman Taylor AJ. Exposure to dust and rat urinary aeroallergens in research establishments. Occup Environ Med 1994;51(9):593-6
  21. Gordon S, Tee RD, Lowson D, Wallace J, Newman Taylor AJ. Reduction of airborne allergenic urinary proteins from laboratory rats. Br J Ind Med 1992;49(6):416-22
  22. Thulin H, Bjorkdahl M, Karlsson AS, Renstrom A. Reduction of exposure to laboratory animal allergens in a research laboratory. Ann Occup Hyg 2002;46(1):61-8
  23. Baur X, Chen Z, Liebers V. Exposure-response relationships of occupational inhalative allergens. Clin Exp Allergy 1998;28(5):537-44
  24. Lieutier-Colas F, Meyer P, Larsson P, Malmberg P, Frossard N, Pauli G, de Blay F. Difference in exposure to airborne major rat allergen (Rat n 1) and to endotoxin in rat quarters according to tasks. Clin Exp Allergy 2001;31(9):1449-56
  25. Gordon S, Tee RD, Newman Taylor AJ. Analysis of the allergenic composition of rat dust. Clin Exp Allergy 1996;26(5):533-41
  26. Spitzauer S, Schweiger C, Sperr WR, Pandjaitan B, Valent P, Muhl S, Ebner C, Scheiner O, Kraft D, Rumpold H, et al. Molecular characterization of dog albumin as a cross-reactive allergen. J Allergy Clin Immunol 1994;93(3):614-27
  27. Mantyjarvi R, Rautiainen J, Virtanen T. Lipocalins as allergens. Biochim Biophys Acta 2000;1482(1-2):308-17
  28. Moller NE, Wurden KV. Allergy to laboratory rats. [Danish] Ugeskr Laeger 1984;146(49):3869-72
  29. Hunskaar S, Fosse RT. Allergy to laboratory mice and rats: a review of the pathophysiology, epidemiology and clinical aspects. Lab Anim 1990;24(4):358-74
  30. Platts-Mills TA, Longbottom J, Edwards J, Heymann PW. Asthma and rhinitis related to laboratory rats: use of a purified rat urinary allergen to study exposure in laboratories and the human immune response. N Engl Reg Allergy Proc 1987;8(4):245-51
  31. Cullinan P, Lowson D, Nieuwenhuijsen MJ, Gordon S, Tee RD, Venables KM, McDonald JC, Newman Taylor AJ. Work related symptoms, sensitisation, and estimated exposure in workers not previously exposed to laboratory rats. Occup Environ Med 1994;51(9):589-92
  32. Hunskar S. Allergy to laboratory animals. A new problem of the occupational environment. [Norwegian] Tidsskr Nor Laegeforen 1989;109(24):2453-5
  33. Hesford JD, Platts-Mills TA, Edlich RF. Anaphylaxis after laboratory rat bite: an occupational hazard. J Emerg Med 1995;13(6):765-8
  34. Heederik D, Venables KM, Malmberg P, Hollander A, Karlsson AS, Renstrom A, Doekes G, Nieuwenhijsen M, Gordon S. Exposure-response relationships for work-related sensitization in workers exposed to rat urinary allergens: results from a pooled study. J Allergy Clin Immunol 1999;103(4):678-84
  35. Hollander A, Heederik D, Doekes G. Respiratory allergy to rats: exposure-response relationships in laboratory animal workers. Am J Respir Crit Care Med 1997;155(2):562-7
  36. Cullinan P, Cook A, Gordon S, Nieuwenhuijsen MJ, Tee RD, Venables KM, McDonald JC, Taylor AJ. Allergen exposure, atopy and smoking as determinants of allergy to rats in a cohort of laboratory employees. Eur Respir J 1999;13(5):1139-43
  37. Gordon S, Tee RD, Nieuwenhuijsen MJ, Lowson D, Harris J, Newman Taylor AJ. Measurement of airborne rat urinary allergen in an epidemiological study. Clin Exp Allergy 1994;24(11):1070-7

 

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.