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The greatest schism in church history occurred between the church of Constantinople and the church of Rome. While 1054 is the symbolic date of the separation, the agonizing division was six centuries in the making and the result of several different issues. The Eastern church sharply disagreed when the Western church introduced into the Nicene Creed the doctrine that the Holy Spirit proceeds not from the Father alone—as earlier Church Fathers had taught—but from the Father and the Son (Latin: Filioque). When the Roman Empire was divided into two zones, Latin-speaking Rome began to claim superiority over Greek-speaking Constantinople, and disputes arose over church boundaries and control (for example, in Illyricum and Bulgaria). Rivalry developed in Slavic regions between Latin missionaries from the West and Byzantine missionaries from the East, who considered this territory to be Orthodox. Disputes over authority became even more heated in the 11th century as Rome asserted its primacy over all churches. Lesser matters related to worship and church discipline—for example, married clergy (Orthodox) versus celibacy (Roman Catholic) and rules of fasting and tonsure—strained ecclesial relations. The tensions became a schism in 1054, when the uncompromising patriarch of Constantinople, Michael Cerularius, and the uncompromising envoys of the pope St. Leo IX excommunicated each other. No act of separation was at this time considered final by either side. Total alienation came a century and a half later, as a result of the Crusades, when Christian knights made military campaigns to save Jerusalem and the Holy Land from the Muslims. In 1204 the Fourth Crusade was diverted to attack and capture Constantinople brutally. Thousands of Orthodox Christians were murdered, churches and icons were desecrated, and undying hostility developed between East and West.

Even so, certain leaders and theologians on both sides tried to heal the breach and reunite East and West. In 1274, at the second Council of Lyon, agreement was reached between the two churches over several key issues—Orthodox acceptance of papal primacy and the acceptance of the Nicene Creed with the Filioque clause. But the agreements were only a rushed action conditioned by political intrigue. As a result, reunion on these terms was fiercely rejected by the clergy and laity in Constantinople and other Orthodox provinces. A second attempt at reunion came at the Council of Ferrara-Florence that met in Italy in 1438 and 1439. A formula of union was approved by both delegations, but later it was rejected by rank-and-file Orthodox Christians.