Introduction 62 66 39 71 62 85 62 62 20 27 77 35 56 59 76 80 82 35 56 80 82 The pathogenic potential unfolded by autoantibodies is determined not only by their specificity and affinity, but also by their isotype. Autoantibodies against cutaneous proteins in autoimmune blistering diseases belong to different IgG subclasses. This paper summarizes the current knowledge on the relevance of IgG subclasses for tissue injury in autoimmune bullous diseases. Pemphigus diseases 39 54 71 62 4 21 45 55 2 5 8 9 16 18 23 28 36 38 40 49 61 79 1 5 17 23 40 52 78 9 42 86 57 29 24 Fig. 1 a d b c  3 50 In conclusion, in pemphigus diseases the autoantibodies mainly belong to the IgG4 and IgG1 subclasses. Extensive experimental evidence demonstrates the blister-inducing potential of IgG4 autoantibodies. The pathogenic activity of autoantibodies of other subclasses seems likely, but needs further investigation. Subepidermal autoimmune blistering diseases Bullous pemphigoid and pemphigoid gestationis 87 62 66 48 65 88 44 84 31 64 1 10 12 22 61 83 10 11 61 83 2 6 19 32 41 69 Fig. 2 lane 1 lane 4 lane 2 lane 3  14 37 53 43 32 3 46 72 4 46 33 70 46 Fig. 3 a b c  Fig. 4 a  b c  58 73 75 58 2+ 73 75 73 2+ 74 Mucous membrane pemphigoid 62 66 7 34 34 34 60 34 60 Diseases associated with autoimmunity against type VII collagen 60 63 67 81 68 7 15 26 47 68 68 13 25 30 51 30 51 51 30 Conclusion and perspectives The polyclonal antibody response against structural skin proteins in autoimmune bullous diseases is heterogeneous, but shows a skewing in subclass distribution of autoantibodies. The strong bias toward production of IgG4 autoantibodies in these organ-specific autoimmune diseases suggests chronic antigenic stimulation. In pemphigus, IgG4 autoantibodies that dominate the autoimmune response are clearly pathogenic. However, IgG1 autoantibodies also likely possess blister-inducing potential that requires further investigation. In subepidermal autoimmune blistering diseases, the effector functions of autoantibodies are important for blistering. Thus, in bullous pemphigoid and epidermolysis bullosa acquisita, complement-fixing IgG1 autoantibodies may show a significantly higher pathogenic potential when compared with IgG4 autoantibodies. Characterization of the blister-inducing capacity of different subclasses of autoantibodies in autoimmune bullous diseases will not only provide relevant mechanistic insights, but should also greatly facilitate the development of improved therapeutic modalities of autoimmune blistering diseases. Detailed knowledge on the pathogenic IgG isotype(s) will serve as a basis for the development of IgG subclass-specific immunoapheresis, skewing autoantibody production toward non-pathogenic subclasses by immunotherapy or blocking of complement or leukocytes activation by targeting specific IgG subclasses. A promising approach is represented by interventions aimed at inhibiting the production of autoantibodies in general or skewing the production of autoantibodies toward non-pathogenic subclasses. The molecular targets of these approaches may include different cytokines (e.g., IL-12 and IL-17) and their activity could be modulated using inhibitory antibodies, small peptide inhibitors or peptidomimetics as well as immunization with the autoantigen together with adjuvants known to induce a Th2 immune response.