Immunosuppression Associated With Immune-Mediated Disorders
M. Julia B. Felippe • Debra C. Sellon
Immune-mediated disorders often cause tissue or cellular damage. One of the outcomes is the potential for immunosuppression and increased risk of secondary infection through a variety of mechanisms, including loss of epithelial barriers, loss of critical immune cellular elements, hormonal imbalances, and dysregulation of immune responses.
Autoimmune disorders comprise a subset of immune-mediated conditions, and selfmolecules become a target in the context of an immune response. The etiology of most autoimmune diseases is uncertain but appears to be related to exposure to an antigen (e.g., infectious organism, tumoral proteins, drugs) and/or an environmental trigger (e.g., chemicals) in an individual animal or human that is genetically susceptible.Aplastic anemia and myelodysplastic syndrome, both associated with autoimmune syndromes in humans, have been reported rarely in the horse.1,2,3 Severe panleukopenia is seen peripherally, whereas significant bone marrow hypocellularity and myeloid maturation arrest are seen in aplastic anemia and myelodysplastic syndrome, respectively. Profound immunosuppression would be expected to occur with such pathology because immune cells involved in all aspects of innate and adaptive immunity are affected.
Autoimmune neutropenia may occur from hypersensitivity mediated by autoantibodies (or isoantibodies) that destroy circulating neutrophils or neutrophil precursors in the bone marrow. These antibodies may be produced as a primary autoimmune disorder secondary to drug administration, infectious disease, or neoplasia. Adult immune-mediated neutropenia has been reported in the dog, generally occurring concurrently with immune-mediated thrombocytopenia and/ or immune-mediated hemolytic anemia, but no similar reports have been described in the horse.4 Destruction of neutrophils has also been reported in alloimmune neonatal neutropenia with the absorption from colostrum of alloantibodies (produced by the dam).
These alloantibodies, once in the foal's circulation, promote opsonization of neonatal neutrophils and enhanced clearance from circulation. The impaired immunity associated with profound neutropenia places these foals at significant risk for sepsis and other serious infections and must be identified early to allow successful intervention. Administration of exogenous granulocyte colony-stimulating factor (G-CSF) is usually necessary because affected foals often do not produce adequate levels of endogenous G-CSF.5 Alloimmune neonatal neutropenia causes moderate to severe neutropenia in neonatal foals and has been reported in conjunction with alloimmune neonatal isoerythrolysis, ulcerative dermatitis, and thrombocytopenia.5-7Reported occasionally in horses, immune-mediated thrombocytopenia has the potential to negatively affect immune responses.8,9 Platelets can play both indirect and direct roles in protecting an animal from infection. They promote antiviral cytotoxic T lymphocyte-mediated responses and contain important antibacterial proteins that when released promote rapid microbial killing.10 Diminished levels of platelet-derived cytokines may affect Th polarization and have a negative impact on bone marrow function.11 Importantly, RBCs from thrombocytopenic mice have demonstrated an increased susceptibility to hemoparasite infection, indicating that thrombocytopenia can have an important in vivo effect on immunocompetency.10
Autoimmune skin disorders causing lesions that impair the skin barrier can predispose affected areas to secondary infection.12 This is primarily a concern with the large bullae and ulceration occurring in pemphigus vulgaris or bullous pemphigoid, but the risk exists for any skin disease that breaches this important physical barrier to infection. Pemphigus foliaceus, paraneoplastic pemphigus, cutaneous (discoid) lupus erythematosus, and systemic lupus erythematosus (SLE) can all cause lesions that may predispose to secondary infection.
This risk may be amplified if the lesions are painful or pruritic, leading to excoriation or self-mutilation. Hence Culicoides hypersensitivity, urticaria, and vasculitis are autoimmune conditions of the skin that can also predispose to secondary infections.In cutaneous vasculitis, most commonly seen in the horse as purpura hemorrhagica, Ag-Ab complexes are deposited in the walls of small blood vessels, and the resultant inflammation is manifested as severe edema, tissue necrosis, and ulceration. Penetration of the skin barrier under this condition may result in a secondary bacterial infection, particularly cellulitis and pneumonia. Therefore prophylactic antimicrobial therapy is often warranted in the treatment of purpura hemorrhagica.13
Systemic lupus erythematosus, rarely reported in horses,14 may impair cutaneous defense to infection and compromise the adaptive immune system. In humans, SLE causes dysregula- tion of apoptosis that leads to premature death of PBMCs, resulting in leukopenia, particularly lymphopenia.15 The functionality of T cells in patients with SLE is impaired, with decreased IL-2 secretion and other factors leading to weakened antiviral immunity.15
Most reports of diabetes mellitus (DM) in the horse have described type 2 (noninsulin-dependent) DM secondary to PPID or equine metabolic syndrome. However, type 1 DM resulting from autoimmune destruction of pancreatic beta cells and subsequent decreased insulin production has been reported.16 In humans, DM is associated with an increased risk of lower respiratory infections, urinary tract infections, and infections of the skin or mucous membranes.17 Abnormal function has been documented in neutrophils, monocytes, and lymphocytes, including decreased adherence, chemotaxis, and intracellular killing, as well as impaired phagocytosis and diminished lymphocyte proliferative response.18 These negative effects have largely been attributed to the impact of poor glycemic control, and it is therefore likely that similar effects could occur with equine DM.