Systemic autoimmune diseases like Systemic Lupus Erythematosus (SLE) and Rheumatoid ƌƚŚƌŝƟƐ (RA) are highly heterogeneous both at the clinical and pathogenic levels. 'ĞnĞƟc͕ environmental, hormonal, ĞƉŝŐĞnĞƟc͕ and immunoregulatory factors are involved within the expression of systemic autoimmune diseases. Recent advances have ŝĚĞnƟĮĞĚ numerous autoimmune-predisposing genomic loci and genes. However, it remains to be elucidated how each gene is involved within the development of disease. Animal models for spontaneous autoimmune disorder have contributed enormously to the ŝĚĞnƟĮcĂƟŽn of genes that are important in disease pathogenesis. Moreover, study of gene-manipulated animals that develop systemic autoimmune diseases has provided insights into the mechanisms of maintenance and breakdown of self-tolerance. Although animal modes don't represent with ĮĚĞůŝƚLJ human disease, they need provide ƐŝŐnŝĮcĂnƚ insights into the ĂbƌŽŐĂƟŽn of selftolerance, the development of autoimmunity, and related organ damage. Animals that developed autoimmunity spontaneously or ĂŌĞƌ gene engineering or ĂŌĞƌ the ŝnũĞcƟŽn of a ƐƟmƵůĂnƚ serve the preclinical studies which seek to work out the clinical ĞĸcĂcLJ of ƌĂƟŽnĂůůLJ developed drugs or biologics . Systemic ŝnŇĂmmĂƚŽƌLJ diseases that regularly ĂīĞcƚ both the central and peripheral nervous systems and may begin with neurological symptoms. These diseases cross ƚƌĂĚŝƟŽnĂů boundaries between neurology and rheumatology, and diagnosis and treatment require familiarity with the spectrum of neurological involvement with interdisciplinary cŽmmƵnŝcĂƟŽn͘ We reviewed a number of the more common neurological mĂnŝĨĞƐƚĂƟŽnƐ of selected autoimmune diseases like systemic lupus erythematosus, Sjogren syndrome, rheumatoid ĂƌƚŚƌŝƟƐ͕ scleroderma, sarcoidosis, primary ĂnŐŝŝƟƐ of the central nervous system, systemic ǀĂƐcƵůŝƟƐ syndromes, and ĂnƟƉŚŽƐƉŚŽůŝƉŝĚ syndrome. We discuss several systemic diseases that have an immunemediated pathogenesis. Although most of those diseases are infrequent and infrequently ĂīĞcƚ the neurological system, clinicians should remain cognizant of their existence. While an in-depth encounter with each of the subsequent diseases is out of the scope of this chapter, we cover the foremost encountered and also the most prominent neurological and clinical mĂnŝĨĞƐƚĂƟŽnƐ to assist guide the clinician into ŝĚĞnƟĨLJŝnŐ͕ diagnosing, and ƚƌĞĂƟnŐ these illnesses. Remarkable discoveries over the last twenty years have elucidated the autoimmune basis of several, previously poorly understood, neurological disorders. Autoimmune disorders of the system may ĂīĞcƚ any part of the system including the brain and medulla spinalis (central systema nervosum, CNS) and also t he peripheral nerves, synapse, and muscle (peripheral system, PNS). This comprehensive overview of this rapidly evolving ĮĞůĚ presents the factors which can trigger breakdown of selftolerance and development of autoimmune disorder in some individuals. Then the pathophysiological basis and clinical features of autoimmune diseases of the systema nervosum are outlined, with a stress on the features which are important to acknowledge for accurate clinical diagnosis. Finally, the most recent therapies for autoimmune CNS and PNS disorders and therefore their mechanisms of ĂcƟŽn and the most promising research avenues for targeted immunotherapy are discussed. The past decade has seen a ĚƌĂmĂƟc increase within the discovery of novel neural ĂnƟbŽĚŝĞƐ and their targets. Many commercial laboratories can now test for these ĂnƟbŽĚŝĞƐ͕ which ĨƵncƟŽn ĚŝĂŐnŽƐƟc markers of diverse neurologic disorders that occur on an autoimmune basis. Some are highly ƐƉĞcŝĮc certainly cancer types, and also the neural ĂnƟbŽĚLJ ƉƌŽĮůĞƐ may help direct the physician's cancer. The diagnosis of an autoimmune neurologic disorder is aided by the ĚĞƚĞcƟŽn of an ŽbũĞcƟǀĞ neurologic ĚĞĮcŝƚ (usually subacute in onset with a ŇƵcƚƵĂƟnŐ course), the presence of a neural ĂƵƚŽĂnƟbŽĚLJ͕ and improvement within the neurologic status ĂŌĞƌ a course of immunotherapy. Neural ĂƵƚŽĂnƟbŽĚŝĞƐ should raise concern for a ƉĂƌĂnĞŽƉůĂƐƟc ĞƟŽůŽŐLJ and will inform a targeted oncologic ĞǀĂůƵĂƟŽn (eg., N-methyl-Daspartate [NMDA] receptor ĂnƟbŽĚŝĞƐ are related to teratoma, ĂnƟnĞƵƌŽnĂů nuclear ĂnƟbŽĚLJ type 1 [ANNA-1, or ĂnƟͲ,Ƶ΁ are related to small cell lung cancer). MRI, EEG, ĨƵncƟŽnĂů imaging, videotaped ĞǀĂůƵĂƟŽnƐ͕ and neuropsychological ĞǀĂůƵĂƟŽnƐ provide ŽbũĞcƟǀĞ evidence of neurologic ĚLJƐĨƵncƟŽn by which the success of immunotherapy could also be measured. Most treatment ŝnĨŽƌmĂƟŽn emanates from ƌĞƚƌŽƐƉĞcƟǀĞ case series and expert opinion. Nonetheless, early ŝnƚĞƌǀĞnƟŽn may allow reversal of ĚĞĮcŝƚƐ in many ƉĂƟĞnƚƐ and ƉƌĞǀĞnƟŽn of future disability.