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Cross-sensitization to milk proteins: Reactivity to a kosher epitope?

Cross-sensitization to milk proteins: Reactivity to a kosher epitope?. Michael Goldberg, MD, PhD Institute of Allergy and Immunology Assaf Harofeh Medical Center. Epidemiology: Who is really allergic?. The literature reports between 2–5% during the first three years of life.

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Cross-sensitization to milk proteins: Reactivity to a kosher epitope?

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  1. Cross-sensitization to milk proteins: Reactivity to a kosher epitope? Michael Goldberg, MD, PhD Institute of Allergy and Immunology Assaf Harofeh Medical Center

  2. Epidemiology: Who is really allergic? • The literature reports between 2–5% during the first three years of life. • The prevalence of self-diagnosed CMA in the community is 10-fold higher than the clinically proven incidence, suggesting a sizable population is unnecessarily eschewing dairy products (J Am Coll Nutr. 2005 Dec;24(6 Suppl):582S-91S ). • True incidence in Israel is less than 0.5% of the population (Katz, et al. JACI abstract 2009). • Near-fatal or fatal outcomes occurs primarily in the older children and adolescents.

  3. Kosher Nonkosher Crossreacting Not Crossreacting

  4. Hypothesis • Milk derived from kosher animals and not from nonkosher animals are reactive in IgE-mediated cow’s milk protein allergy (Katz, et al. Isr Med Assoc J. 10:1-4.)

  5. SKIN PRICK TEST (SPT) Cow`s milk allergy or drug allergy ????

  6. SPT results in cow’s milk protein allergic patients Wheal/flare (Katz, et al. Isr Med Assoc J. 10:1-4.)

  7. SPT results in Control Group (Katz, et al. Isr Med Assoc J. 10:1-4.)

  8. Cow [24/24 + 47/47] Buffalo [24/24] Goat [46/47] Ibex [24/24+46/47] Deer [24/24] Giraffe [46/47] Camel [2/8+8/47] Pig [5/24 +12/47] Rabbit [4/47] Dog [16/47] Horse [3/42] Alpaca [10/47] Cross reactivity of CMP with proteins from milk of other animals – response to Non- Kosher “age dependent” Kosher – Cross * Allergenicity Non Kosher – No Cross Allergenicity ** • * p = 0.02 (Fisher test) • ** p > 0.35

  9. Cow [24/24 + 47/47] Buffalo [24/24] Goat [46/47] Ibex [24/24+46/47] Deer [24/24] Giraffe [46/47] Camel [2/8+8/47] 1/8 Pig [5/24 +12/47] 1/11 # Rabbit [4/47] 0/4 Dog [16/47] 4/12 ## Horse [3/42] 0/3 Alpaca [10/47] 1/9 Cross reactivity of CMP with proteins from milk of other animals – response to Non- Kosher “age dependent” Below 30 m/ over 30 m Kosher – Cross * Allergenicity Non Kosher – No Cross Allergenicity ** • * p = 0.02 (Fisher test) • ** p > 0.35 Logistic regression for moth of life # OR= 1.008, ## OR=1.026

  10. Is there a common epitope found only in kosher animals?

  11. Main characteristics of the bovine milk proteins Wal, JM. Ann Allergy Asthma Immunol. 2004

  12. Beta-lactoglobulin

  13. Beta-Casein

  14. Alpha-lactalbumin

  15. Cow Buffalo Deer Ibex Sheep Camel Horse Pig Human Camel Horse Pig Human

  16. This eight amino acid sequence creates a completely new structure C=C C

  17. Schematic model of kappa-casein multimers in bovine and human milk Rasmusssen, International Dairy Journal, 1999

  18. VPAKSCQA/D-Sequence responsible for allergenicity? Hypothesis • Aggregation of casein monomers reveals new determinants that seem to be absent in the monomeric forms, since some sera show IgE reactivity only against aggregates, but not against individual components (Allergy. 1996; Jun;51(6):412-6) • When bovine kappa-casein was expressed in the mouse a a different micellar structure was noted (J Dairy Sci 79:791-799, 1996) • This region may therefore lead to the generation of multiple allergenic epitopes in susceptible individuals.

  19. Approach • Structural analysis of the native and mutated kappa casein • Modeling • Limited proteolytic digestion maintaining the disulfide bond intact • Generation of wildtype and mutated kappa-casein • In vitro-mammalian expression systems • In vivo- transgenic mouse lines • Analyze mutated kappa-casein both by SPT on milk-allergic patients and their sera for IgE binding antibodies

  20. Ser88

  21. Trypsin digests reveals Arg at #97 and Lys at 111 & 112 are sensitive sites

  22. Chymosin digestion of kappa-casein

  23. Difference in micellar structure between wildtype mice and mice carrying bovine kappa-casein gene • Milk derived from transgenic mice with the bovine kappa-casein gene form a stronger curd.

  24. Acknowledgements • Yitzhak Katz, Director, Institute of Allergy and Immunology, Assaf Harofeh Medical Center • Richard Friedman, Columbia University, NY • Menachem Shoham, Case Western University • Alberto Huberman, University of Mexico, UNAM • James D. Murray, UC Davis • Elizabeth Maga, UC Davis Funded by: קרן המחקר של מועצת החלב

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