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The three principal causes of bacterial meningitis, Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae, produce an IgA1 protease. In addition, IgA1 proteases are produced by two urogenital pathogens, five species of commensal gram-positive cocci found in the pharynx and oral cavity, H. parahaemolyticus, and all human-associated species of the genera Capnocytophaga and Prevotella. In accordance with the substrate specificity of IgA1 proteases, humans and hominoid primates are the exclusive hosts of the bacteria that produce these enzymes. This chapter presents the hypothesis that invasive infection in occasional individuals is a result of nonsynchronized induction of the two types of antibodies by successive encounters with two different microorganisms: (i) colonization in the gut or upper respiratory tract with bacteria expressing surface epitopes similar or identical to those of the respective pathogen (e.g., E. coli K100 in the case of H. influenzae type b, and E. coli K1 or Moraxella nonliquefaciens in the case of N. meningitidis group B), and (ii) subsequent colonization with the actual pathogen. As a result of the prior colonization with a cross-reactive microorganism, the pathogen encounters preexisting IgA1 antibodies to its surface epitopes but no antibodies that will neutralize its IgA1 protease. IgA1s of humans and hominoid primates were the only known substrates of IgA1 proteases until recently. Now other permissive substrates have been revealed. Most of these are proteins of immunological relevance, but for some of the substrates, their accessibility to IgA1 protease in vivo is a matter of speculation.